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1
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Gibhard L, Njoroge M, Mulubwa M, Lawrence N, Smith D, Duffy J, Le Manach C, Brunschwig C, Taylor D, van der Westhuyzen R, Street LJ, Basarab GS, Chibale K. Dose-fractionation studies of a Plasmodium phosphatidylinositol 4-kinase inhibitor in a humanized mouse model of malaria. Antimicrob Agents Chemother 2024; 68:e0084224. [PMID: 39194209 PMCID: PMC11459969 DOI: 10.1128/aac.00842-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 08/09/2024] [Indexed: 08/29/2024] Open
Abstract
UCT594 is a 2-aminopyrazine carboxylic acid Plasmodium phosphatidylinositol 4-kinase inhibitor with potent asexual blood-stage activity, the potential for interrupting transmission, as well as liver-stage activities. Herein, we investigated pharmacokinetic/pharmacodynamic (PK/PD) relationships relative to blood-stage activity toward predicting the human dose. Dose-fractionation studies were conducted in the Plasmodium falciparum NSG mouse model to determine the PK/PD indices of UCT594, using the in vivo minimum parasiticidal concentration as a threshold. UCT594 demonstrated concentration-dependent killing in the P. falciparum-infected NSG mouse model. Using this data and the preclinical pharmacokinetic data led to a low predicted human dose of <50 mg. This makes UCT594 an attractive potential antimalarial drug.
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Affiliation(s)
- Liezl Gibhard
- Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, South Africa
| | - Mathew Njoroge
- Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, South Africa
| | - Mwila Mulubwa
- Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, South Africa
| | - Nina Lawrence
- Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, South Africa
| | | | - James Duffy
- Medicines for Malaria Venture, ICC, Geneva, Switzerland
| | - Claire Le Manach
- Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, South Africa
| | - Christel Brunschwig
- Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, South Africa
| | - Dale Taylor
- Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, South Africa
| | - Renier van der Westhuyzen
- Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, South Africa
| | - Leslie J. Street
- Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, South Africa
| | - Gregory S. Basarab
- Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, South Africa
| | - Kelly Chibale
- Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, South Africa
- South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, South Africa
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Muh F, Erwina A, Fitriana F, Syahada JH, Cahya AD, Choe S, Jun H, Garjito TA, Siregar JE, Han JH. Plasmodium cynomolgi: What Should We Know? Microorganisms 2024; 12:1607. [PMID: 39203449 PMCID: PMC11356028 DOI: 10.3390/microorganisms12081607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 07/31/2024] [Accepted: 08/01/2024] [Indexed: 09/03/2024] Open
Abstract
Even though malaria has markedly reduced its global burden, it remains a serious threat to people living in or visiting malaria-endemic areas. The six Plasmodium species (Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale curtisi, Plasmodium ovale wallikeri and Plasmodium knowlesi) are known to associate with human malaria by the Anopheles mosquito. Highlighting the dynamic nature of malaria transmission, the simian malaria parasite Plasmodium cynomolgi has recently been transferred to humans. The first human natural infection case of P. cynomolgi was confirmed in 2011, and the number of cases is gradually increasing. It is assumed that it was probably misdiagnosed as P. vivax in the past due to its similar morphological features and genome sequences. Comprehensive perspectives that encompass the relationships within the natural environment, including parasites, vectors, humans, and reservoir hosts (macaques), are required to understand this zoonotic malaria and prevent potential unknown risks to human health.
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Affiliation(s)
- Fauzi Muh
- Department of Epidemiology and Tropical Diseases, Faculty of Public Health, Universitas Diponegoro, Semarang 50275, Indonesia; (F.M.); (A.E.); (F.F.); (J.H.S.)
| | - Ariesta Erwina
- Department of Epidemiology and Tropical Diseases, Faculty of Public Health, Universitas Diponegoro, Semarang 50275, Indonesia; (F.M.); (A.E.); (F.F.); (J.H.S.)
| | - Fadhila Fitriana
- Department of Epidemiology and Tropical Diseases, Faculty of Public Health, Universitas Diponegoro, Semarang 50275, Indonesia; (F.M.); (A.E.); (F.F.); (J.H.S.)
| | - Jadidan Hada Syahada
- Department of Epidemiology and Tropical Diseases, Faculty of Public Health, Universitas Diponegoro, Semarang 50275, Indonesia; (F.M.); (A.E.); (F.F.); (J.H.S.)
| | - Angga Dwi Cahya
- Department of Environmental Health, Faculty of Public Health, Universitas Diponegoro, Semarang 50275, Indonesia;
| | - Seongjun Choe
- Department of Parasitology, School of Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea;
| | - Hojong Jun
- Department of Environmental Biology and Tropical Medicine, School of Medicine, Kangwon National University, Chuncheon 24341, Republic of Korea;
| | - Triwibowo Ambar Garjito
- Vector-Borne and Zoonotic Research Group, Research Center for Public Health and Nutrition, National Research and Innovation Agency Indonesia, Salatiga 50721, Indonesia;
| | - Josephine Elizabeth Siregar
- Eijkman Research Center for Molecular Biology, National Research and Innovation Agency, Jalan Raya Bogor Km. 46, Cibinong, Bogor 16911, Indonesia;
| | - Jin-Hee Han
- Department of Environmental Biology and Tropical Medicine, School of Medicine, Kangwon National University, Chuncheon 24341, Republic of Korea;
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Voorberg-van der Wel A, Zeeman AM, Kocken CHM. Transfection Models to Investigate Plasmodium vivax-Type Dormant Liver Stage Parasites. Pathogens 2023; 12:1070. [PMID: 37764878 PMCID: PMC10534883 DOI: 10.3390/pathogens12091070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 08/17/2023] [Accepted: 08/21/2023] [Indexed: 09/29/2023] Open
Abstract
Plasmodium vivax causes the second highest number of malaria morbidity and mortality cases in humans. Several biological traits of this parasite species, including the formation of dormant stages (hypnozoites) that persist inside the liver for prolonged periods of time, present an obstacle for intervention measures and create a barrier for the elimination of malaria. Research into the biology of hypnozoites requires efficient systems for parasite transmission, liver stage cultivation and genetic modification. However, P. vivax research is hampered by the lack of an in vitro blood stage culture system, rendering it reliant on in vivo-derived, mainly patient, material for transmission and liver stage culture. This has also resulted in limited capability for genetic modification, creating a bottleneck in investigations into the mechanisms underlying the persistence of the parasite inside the liver. This bottleneck can be overcome through optimal use of the closely related and experimentally more amenable nonhuman primate (NHP) parasite, Plasmodium cynomolgi, as a model system. In this review, we discuss the genetic modification tools and liver stage cultivation platforms available for studying P. vivax persistent stages and highlight how their combined use may advance our understanding of hypnozoite biology.
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Affiliation(s)
- Annemarie Voorberg-van der Wel
- Department of Parasitology, Biomedical Primate Research Centre, 2288 GJ Rijswijk, The Netherlands; (A.-M.Z.); (C.H.M.K.)
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Plasmodium cynomolgi in humans: current knowledge and future directions of an emerging zoonotic malaria parasite. Infection 2022; 51:623-640. [PMID: 36401673 PMCID: PMC9676733 DOI: 10.1007/s15010-022-01952-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 11/01/2022] [Indexed: 11/21/2022]
Abstract
Plasmodium cynomolgi (Pcy), a simian malaria parasite, is a recent perfect example of emerging zoonotic transfer in human. This review summarizes the current knowledge on the epidemiology of natural Pcy infections in humans, mosquitoes and monkeys, along with its biological, clinical and drug sensitivity patterns. Knowledge gaps and further studies on Pcy in humans are also discussed. This parasite currently seems to be geographically limited in South-East Asia (SEA) with a global prevalence in human ranging from 0 to 1.4%. The Pcy infections were reported in local SEA populations and European travelers, and range from asymptomatic carriage to mild/moderate attacks with no evidence of pathognomonic clinical and laboratory patterns but with Pcy strain-shaped clinical differences. Geographical distribution and competence of suitable mosquito vectors and non-primate hosts, globalization, climate change, and increased intrusion of humans into the habitat of monkeys are key determinants to emergence of Pcy parasites in humans, along with its expansion outside SEA. Sensitization/information campaigns coupled with training and assessment sessions of microscopists and clinicians on Pcy are greatly needed to improve data on the epidemiology and management of human Pcy infection. There is a need for development of sensitive and specific molecular tools for individual diagnosis and epidemiological studies. The development of safe and efficient anti-hypnozoite drugs is the main therapeutic challenge for controlling human relapsing malaria parasites. Experience gained from P. knowlesi malaria, development of integrated measures and strategies—ideally with components related to human, monkeys, mosquito vectors, and environment—could be very helpful to prevent emergence of Pcy malaria in humans through disruption of transmission chain from monkeys to humans and ultimately contain its expansion in SEA and potential outbreaks in a context of malaria elimination.
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Sterile protection against relapsing malaria with a single-shot vaccine. NPJ Vaccines 2022; 7:126. [PMID: 36302860 DOI: 10.1038/s41541-022-00555-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 10/11/2022] [Indexed: 11/08/2022] Open
Abstract
Vaccine development for Plasmodium vivax, an important human relapsing malaria, is lagging behind. In the case of the most deadly human malaria P. falciparum, unprecedented high levels of protection have been obtained by immunization with live sporozoites under accompanying chemoprophylaxis, which prevents the onset of blood-stage malaria. Such an approach has not been fully evaluated for relapsing malaria. Here, in the P. cynomolgi-rhesus macaque model for relapsing malaria, we employ the parasites' natural relapsing phenotype to self-boost the immune response against liver-stage parasites, following a single-shot high-dose live sporozoite vaccination. This approach resulted in sterile protection against homologous sporozoite challenge in three out of four animals in the group that was also exposed for several days to blood stages during primary infection and relapses. One out of four animals in the group that received continuous chemoprophylaxis to abort blood-stage exposure was also protected from sporozoite challenge. Although obtained in a small number of animals as part of a Proof-of-Concept study, these results suggest that limited blood-stage parasite exposure may augment protection in this model. We anticipate our data are a starting point for further research into correlates of protection and extrapolation of the single-shot approach to develop efficacious malaria vaccines against relapsing human malaria.
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Flannery EL, Kangwanrangsan N, Chuenchob V, Roobsoong W, Fishbaugher M, Zhou K, Billman ZP, Martinson T, Olsen TM, Schäfer C, Campo B, Murphy SC, Mikolajczak SA, Kappe SH, Sattabongkot J. Plasmodium vivax latent liver infection is characterized by persistent hypnozoites, hypnozoite-derived schizonts, and time-dependent efficacy of primaquine. Mol Ther Methods Clin Dev 2022; 26:427-440. [PMID: 36092359 PMCID: PMC9418049 DOI: 10.1016/j.omtm.2022.07.016] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/31/2022] [Indexed: 01/13/2023]
Abstract
Plasmodium vivax is a malaria-causing pathogen that establishes a dormant form in the liver (the hypnozoite), which can activate weeks, months, or years after the primary infection to cause a relapse, characterized by secondary blood-stage infection. These asymptomatic and undetectable latent liver infections present a significant obstacle to the goal of global malaria eradication. We use a human liver-chimeric mouse model (FRG huHep) to study P. vivax hypnozoite latency and activation in an in vivo model system. Functional activation of hypnozoites and formation of secondary schizonts is demonstrated by first eliminating primary liver schizonts using a schizont-specific antimalarial tool compound, and then measuring recurrence of secondary liver schizonts in the tissue and an increase in parasite RNA within the liver. We also reveal that, while primaquine does not immediately eliminate hypnozoites from the liver, it arrests developing schizonts and prevents activation of hypnozoites, consistent with its clinical activity in humans. Our findings demonstrate that the FRG huHep model can be used to study the biology of P. vivax infection and latency and assess the activity of anti-relapse drugs.
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Affiliation(s)
- Erika L. Flannery
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA 98109, USA
- Corresponding author Erika L. Flannery, Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA 98109, USA.
| | - Niwat Kangwanrangsan
- Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Vorada Chuenchob
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA 98109, USA
| | - Wanlapa Roobsoong
- Mahidol Vivax Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Matthew Fishbaugher
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA 98109, USA
| | - Kevin Zhou
- Department of Laboratory Medicine and Pathology, and Department of Microbiology, University of Washington, Seattle, WA 98115, USA
| | - Zachary P. Billman
- Department of Laboratory Medicine and Pathology, and Department of Microbiology, University of Washington, Seattle, WA 98115, USA
| | - Thomas Martinson
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA 98109, USA
| | - Tayla M. Olsen
- Department of Laboratory Medicine and Pathology, and Department of Microbiology, University of Washington, Seattle, WA 98115, USA
| | - Carola Schäfer
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA 98109, USA
| | - Brice Campo
- Medicines for Malaria Venture, Geneva, Switzerland
| | - Sean C. Murphy
- Department of Laboratory Medicine and Pathology, and Department of Microbiology, University of Washington, Seattle, WA 98115, USA
| | - Sebastian A. Mikolajczak
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA 98109, USA
| | - Stefan H.I. Kappe
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA 98109, USA
- Department of Pediatrics, University of Washington, Seattle, WA 98105, USA
- Corresponding author Stefan H.I. Kappe, Department of Pediatrics, University of Washington, Seattle, WA 98105, USA.
| | - Jetsumon Sattabongkot
- Mahidol Vivax Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- Corresponding author Jetsumon Sattabongkot, Mahidol Vivax Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
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7
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Dong Y, Sonawane Y, Maher SP, Zeeman AM, Chaumeau V, Vantaux A, Cooper CA, Chiu FCK, Ryan E, McLaren J, Chen G, Wittlin S, Witkowski B, Nosten F, Sriraghavan K, Kyle DE, Kocken CHM, Charman SA, Vennerstrom JL. Metabolic, Pharmacokinetic, and Activity Profile of the Liver Stage Antimalarial (RC-12). ACS OMEGA 2022; 7:12401-12411. [PMID: 35449901 PMCID: PMC9016807 DOI: 10.1021/acsomega.2c01099] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 03/18/2022] [Indexed: 06/14/2023]
Abstract
The catechol derivative RC-12 (WR 27653) (1) is one of the few non-8-aminoquinolines with good activity against hypnozoites in the gold-standard Plasmodium cynomolgi-rhesus monkey (Macaca mulatta) model, but in a small clinical trial, it had no efficacy against Plasmodium vivax hypnozoites. In an attempt to better understand the pharmacokinetic and pharmacodynamic profile of 1 and to identify potential active metabolites, we now describe the phase I metabolism, rat pharmacokinetics, and in vitro liver-stage activity of 1 and its metabolites. Compound 1 had a distinct metabolic profile in human vs monkey liver microsomes, and the data suggested that the O-desmethyl, combined O-desmethyl/N-desethyl, and N,N-didesethyl metabolites (or a combination thereof) could potentially account for the superior liver stage antimalarial efficacy of 1 in rhesus monkeys vs that seen in humans. Indeed, the rate of metabolism was considerably lower in human liver microsomes in comparison to rhesus monkey microsomes, as was the formation of the combined O-desmethyl/N-desethyl metabolite, which was the only metabolite tested that had any activity against liver-stage P. vivax; however, it was not consistently active against liver-stage P. cynomolgi. As 1 and all but one of its identified Phase I metabolites had no in vitro activity against P. vivax or P. cynomolgi liver-stage malaria parasites, we suggest that there may be additional unidentified active metabolites of 1 or that the exposure of 1 achieved in the reported unsuccessful clinical trial of this drug candidate was insufficient to kill the P. vivax hypnozoites.
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Affiliation(s)
- Yuxiang Dong
- College
of Pharmacy, University of Nebraska Medical
Center, 986125 Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Yogesh Sonawane
- College
of Pharmacy, University of Nebraska Medical
Center, 986125 Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Steven P. Maher
- Center
for Tropical and Emerging Global Diseases, University of Georgia, 370 Coverdell
Center, 500 D.W. Brooks Drive, Athens, Georgia 30602, United States
| | - Anne-Marie Zeeman
- Department
of Parasitology, Biomedical Primate Research
Centre, P.O. Box 3306, 2280 GH Rijswijk, The Netherlands
| | - Victor Chaumeau
- Shoklo
Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit,
Faculty of Tropical Medicine, Mahidol University, 68/30 Bantung Road, Mae Sot, Tak 63110, Thailand
- Centre for
Tropical Medicine and Global Health, Nuffield Department of Medicine
Research building, University of Oxford
Old Road Campus, Oxford OX3 7DQ, U.K.
| | - Amélie Vantaux
- Malaria
Molecular Epidemiology Unit, Institut Pasteur
du Cambodge, 5 Boulevard Monivong, P.O. Box 983, Phnom
Penh 120 210, Cambodia
| | - Caitlin A. Cooper
- Center
for Tropical and Emerging Global Diseases, University of Georgia, 370 Coverdell
Center, 500 D.W. Brooks Drive, Athens, Georgia 30602, United States
| | - Francis C. K. Chiu
- Centre
for Drug Candidate Optimisation, Monash Institute of Pharmaceutical
Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
| | - Eileen Ryan
- Centre
for Drug Candidate Optimisation, Monash Institute of Pharmaceutical
Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
| | - Jenna McLaren
- Centre
for Drug Candidate Optimisation, Monash Institute of Pharmaceutical
Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
| | - Gong Chen
- Centre
for Drug Candidate Optimisation, Monash Institute of Pharmaceutical
Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
| | - Sergio Wittlin
- Department
of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002 Basel, Switzerland
| | - Benoît Witkowski
- Malaria
Molecular Epidemiology Unit, Institut Pasteur
du Cambodge, 5 Boulevard Monivong, P.O. Box 983, Phnom
Penh 120 210, Cambodia
| | - François Nosten
- Shoklo
Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit,
Faculty of Tropical Medicine, Mahidol University, 68/30 Bantung Road, Mae Sot, Tak 63110, Thailand
- Centre for
Tropical Medicine and Global Health, Nuffield Department of Medicine
Research building, University of Oxford
Old Road Campus, Oxford OX3 7DQ, U.K.
| | - Kamaraj Sriraghavan
- College
of Pharmacy, University of Nebraska Medical
Center, 986125 Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Dennis E. Kyle
- Center
for Tropical and Emerging Global Diseases, University of Georgia, 370 Coverdell
Center, 500 D.W. Brooks Drive, Athens, Georgia 30602, United States
| | - Clemens H. M. Kocken
- Department
of Parasitology, Biomedical Primate Research
Centre, P.O. Box 3306, 2280 GH Rijswijk, The Netherlands
| | - Susan A. Charman
- Centre
for Drug Candidate Optimisation, Monash Institute of Pharmaceutical
Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
| | - Jonathan L. Vennerstrom
- College
of Pharmacy, University of Nebraska Medical
Center, 986125 Nebraska Medical Center, Omaha, Nebraska 68198, United States
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Adebayo J, Ceravolo I, Gyebi G, Olorundare E, Babatunde A, Penna-Coutinho J, Koketsu M, Krettli A. Iloneoside, an antimalarial pregnane glycoside isolated from Gongronema latifolium leaf, potentiates the activity of chloroquine against multidrug resistant Plasmodium falciparum. Mol Biochem Parasitol 2022; 249:111474. [DOI: 10.1016/j.molbiopara.2022.111474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 03/09/2022] [Accepted: 03/13/2022] [Indexed: 10/18/2022]
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The Novel bis-1,2,4-Triazine MIPS-0004373 Demonstrates Rapid and Potent Activity against All Blood Stages of the Malaria Parasite. Antimicrob Agents Chemother 2021; 65:e0031121. [PMID: 34460304 DOI: 10.1128/aac.00311-21] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Novel bis-1,2,4-triazine compounds with potent in vitro activity against Plasmodium falciparum parasites were recently identified. The bis-1,2,4-triazines represent a unique antimalarial pharmacophore and are proposed to act by a novel but as-yet-unknown mechanism of action. This study investigated the activity of the bis-1,2,4-triazine MIPS-0004373 across the mammalian life cycle stages of the parasite and profiled the kinetics of activity against blood and transmission stage parasites in vitro and in vivo. MIPS-0004373 demonstrated rapid and potent activity against P. falciparum, with excellent in vitro activity against all asexual blood stages. Prolonged in vitro drug exposure failed to generate stable resistance de novo, suggesting a low propensity for the emergence of resistance. Excellent activity was observed against sexually committed ring stage parasites, but activity against mature gametocytes was limited to inhibiting male gametogenesis. Assessment of liver stage activity demonstrated good activity in an in vitro P. berghei model but no activity against Plasmodium cynomolgi hypnozoites or liver schizonts. The bis-1,2,4-triazine MIPS-0004373 efficiently cleared an established P. berghei infection in vivo, with efficacy similar to that of artesunate and chloroquine and a recrudescence profile comparable to that of chloroquine. This study demonstrates the suitability of bis-1,2,4-triazines for further development toward a novel treatment for acute malaria.
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10
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Vythilingam I, Chua TH, Liew JWK, Manin BO, Ferguson HM. The vectors of Plasmodium knowlesi and other simian malarias Southeast Asia: challenges in malaria elimination. ADVANCES IN PARASITOLOGY 2021; 113:131-189. [PMID: 34620382 DOI: 10.1016/bs.apar.2021.08.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Plasmodium knowlesi, a simian malaria parasite of great public health concern has been reported from most countries in Southeast Asia and exported to various countries around the world. Currently P. knowlesi is the predominant species infecting humans in Malaysia. Besides this species, other simian malaria parasites such as P. cynomolgi and P. inui are also infecting humans in the region. The vectors of P. knowlesi and other Asian simian malarias belong to the Leucosphyrus Group of Anopheles mosquitoes which are generally forest dwelling species. Continual deforestation has resulted in these species moving into forest fringes, farms, plantations and human settlements along with their macaque hosts. Limited studies have shown that mosquito vectors are attracted to both humans and macaque hosts, preferring to bite outdoors and in the early part of the night. We here review the current status of simian malaria vectors and their parasites, knowledge of vector competence from experimental infections and discuss possible vector control measures. The challenges encountered in simian malaria elimination are also discussed. We highlight key knowledge gaps on vector distribution and ecology that may impede effective control strategies.
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Affiliation(s)
- Indra Vythilingam
- Department of Parasitology, University of Malaya, Kuala Lumpur, Malaysia.
| | - Tock Hing Chua
- Department of Pathobiology and Microbiology, Faculty of Medicine and Health Sciences, Universiti Sabah Malaysia, Kota Kinabalu, Sabah, Malaysia.
| | - Jonathan Wee Kent Liew
- Department of Parasitology, University of Malaya, Kuala Lumpur, Malaysia; Environmental Health Institute, National Environment Agency, Singapore, Singapore
| | - Benny O Manin
- Department of Pathobiology and Microbiology, Faculty of Medicine and Health Sciences, Universiti Sabah Malaysia, Kota Kinabalu, Sabah, Malaysia
| | - Heather M Ferguson
- Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow, Scotland, United Kingdom
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11
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Li YP, Mikrani R, Hu YF, Faran Ashraf Baig MM, Abbas M, Akhtar F, Xu M. Research progress of phosphatidylinositol 4-kinase and its inhibitors in inflammatory diseases. Eur J Pharmacol 2021; 907:174300. [PMID: 34217706 DOI: 10.1016/j.ejphar.2021.174300] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 06/24/2021] [Accepted: 06/30/2021] [Indexed: 01/08/2023]
Abstract
Phosphatidylinositol 4-kinase (PI4K) is a lipid kinase that can catalyze the transfer of phosphate group from ATP to the inositol ring of phosphatidylinositol (PtdIns) resulting in the phosphorylation of PtdIns at 4-OH sites, to generate phosphatidylinositol 4-phosphate (PI4P). Studies on biological functions reveal that PI4K is closely related to the occurrence and development of various inflammatory diseases such as obesity, cancer, viral infections, malaria, Alzheimer's disease, etc. PI4K-related inhibitors have been found to have the effects of inhibiting virus replication, anti-cancer, treating malaria and reducing rejection in organ transplants, among which MMV390048, an anti-malaria drug, has entered phase II clinical trial. This review discusses the classification, structure, distribution and related inhibitors of PI4K and their role in the progression of cancer, viral replication, and other inflammation induced diseases to explore their potential as therapeutic targets.
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Affiliation(s)
- Yan-Ping Li
- Department of Clinical Pharmacy, School of Preclinical Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Reyaj Mikrani
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria 3052, Australia
| | - Yi-Fan Hu
- Department of Clinical Pharmacy, School of Preclinical Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Mirza Muhammad Faran Ashraf Baig
- Laboratory of Biomedical Engineering for Novel Bio-functional and Pharmaceutical Nano-materials, Prince Philip Dental Hospital, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, 999077, China
| | - Muhammad Abbas
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210023, PR China
| | - Fahad Akhtar
- State Key Laboratory of Molecular Development Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China; School of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ming Xu
- Department of Clinical Pharmacy, School of Preclinical Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
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12
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Efforts Made to Eliminate Drug-Resistant Malaria and Its Challenges. BIOMED RESEARCH INTERNATIONAL 2021; 2021:5539544. [PMID: 34497848 PMCID: PMC8421183 DOI: 10.1155/2021/5539544] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 08/09/2021] [Indexed: 01/01/2023]
Abstract
Since 2000, a good deal of progress has been made in malaria control. However, there is still an unacceptably high burden of the disease and numerous challenges limiting advancement towards its elimination and ultimate eradication. Among the challenges is the antimalarial drug resistance, which has been documented for almost all antimalarial drugs in current use. As a result, the malaria research community is working on the modification of existing treatments as well as the discovery and development of new drugs to counter the resistance challenges. To this effect, many products are in the pipeline and expected to be marketed soon. In addition to drug and vaccine development, mass drug administration (MDA) is under scientific scrutiny as an important strategy for effective utilization of the developed products. This review discusses the challenges related to malaria elimination, ongoing approaches to tackle the impact of drug-resistant malaria, and upcoming antimalarial drugs.
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13
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Zanghi G, Vaughan AM. Plasmodium vivax pre-erythrocytic stages and the latent hypnozoite. Parasitol Int 2021; 85:102447. [PMID: 34474178 DOI: 10.1016/j.parint.2021.102447] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 08/24/2021] [Accepted: 08/26/2021] [Indexed: 02/02/2023]
Abstract
Plasmodium vivax is the most geographically widespread malaria parasite on the planet. This is largely because after mosquito transmission, P. vivax sporozoites can invade hepatocytes and form latent liver stages known as hypnozoites. These persistent liver stages can activate weeks, months or even years after an infected individual suffers a primary clinical infection. Activation then leads to replication and liver stage schizont maturation that ultimately cause relapse of blood stage infection, disease, and onward transmission. Thus, the latent hypnozoite can lie in wait during times when onward transmission is unlikely due to conditions that do not favor the mosquito. For example, in temperate climates where mosquito prevalence is only seasonal. Furthermore, the elimination of hypnozoites is challenging since the hypnozoite reservoir is currently undetectable and not killed by most antimalarial drugs. Here, we review our current knowledge of the pre-erythrocytic stages of the malaria parasite - the sporozoite and liver stages, including the elusive and enigmatic hypnozoite. We focus on our understanding of sporozoite biology, the novel animal models that are available to study the hypnozoite and hypnozoite activation and the ongoing efforts to understand the biological makeup of the hypnozoite that allow for its persistence in the human host.
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Affiliation(s)
| | - Ashley M Vaughan
- Seattle Children's Research Institute, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA.
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14
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Schäfer C, Zanghi G, Vaughan AM, Kappe SHI. Plasmodium vivax Latent Liver Stage Infection and Relapse: Biological Insights and New Experimental Tools. Annu Rev Microbiol 2021; 75:87-106. [PMID: 34196569 DOI: 10.1146/annurev-micro-032421-061155] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Plasmodium vivax is the most widespread human malaria parasite, in part because it can form latent liver stages known as hypnozoites after transmission by female anopheline mosquitoes to human hosts. These persistent stages can activate weeks, months, or even years after the primary clinical infection; replicate; and initiate relapses of blood stage infection, which causes disease and recurring transmission. Eliminating hypnozoites is a substantial obstacle for malaria treatment and eradication since the hypnozoite reservoir is undetectable and unaffected by most antimalarial drugs. Importantly, in some parts of the globe where P. vivax malaria is endemic, as many as 90% of P. vivax blood stage infections are thought to be relapses rather than primary infections, rendering the hypnozoite a major driver of P. vivax epidemiology. Here, we review the biology of the hypnozoite and recent discoveries concerning this enigmatic parasite stage. We discuss treatment and prevention challenges, novel animal models to study hypnozoites and relapse, and hypotheses related to hypnozoite formation and activation. Expected final online publication date for the Annual Review of Microbiology, Volume 75 is October 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Carola Schäfer
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington 98109, USA; , , ,
| | - Gigliola Zanghi
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington 98109, USA; , , ,
| | - Ashley M Vaughan
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington 98109, USA; , , , .,Department of Pediatrics, University of Washington, Seattle, Washington 98105, USA
| | - Stefan H I Kappe
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington 98109, USA; , , , .,Department of Pediatrics, University of Washington, Seattle, Washington 98105, USA.,Deparment of Global Health, University of Washington, Seattle, Washington 98195, USA
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15
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der Wel AVV, Hofman SO, Kocken CHM. Isolation of GFP-expressing Malarial Hypnozoites by Flow Cytometry Cell Sorting. Bio Protoc 2021; 11:e4006. [PMID: 34124306 DOI: 10.21769/bioprotoc.4006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 02/14/2021] [Accepted: 03/19/2021] [Indexed: 11/02/2022] Open
Abstract
Hypnozoites are dormant liver-stage parasites unique to relapsing malarial species, including the important human pathogen Plasmodium vivax, and pose a barrier to the elimination of malaria. Little is known regarding the biology of these stages, largely due to their inaccessible location. Hypnozoites can be cultured in vitro but these cultures always consist of a mixture of hepatocytes, developing forms, and hypnozoites. Here, using a GFP-expressing line of the hypnozoite model parasite Plasmodium cynomolgi, we describe a protocol for the FACS-based isolation of malarial hypnozoites. The purified hypnozoites can be used for a range of '-omics' studies to dissect the biology of this cryptic stage of the malarial life cycle.
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Affiliation(s)
| | - Sam O Hofman
- Department of Parasitology, Biomedical Primate Research Centre, 2288 GJ Rijswijk, The Netherlands
| | - Clemens H M Kocken
- Department of Parasitology, Biomedical Primate Research Centre, 2288 GJ Rijswijk, The Netherlands
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16
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Voorberg-van der Wel A, Kocken CHM, Zeeman AM. Modeling Relapsing Malaria: Emerging Technologies to Study Parasite-Host Interactions in the Liver. Front Cell Infect Microbiol 2021; 10:606033. [PMID: 33585277 PMCID: PMC7878928 DOI: 10.3389/fcimb.2020.606033] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 12/04/2020] [Indexed: 01/03/2023] Open
Abstract
Recent studies of liver stage malaria parasite-host interactions have provided exciting new insights on the cross-talk between parasite and its mammalian (predominantly rodent) host. We review the latest state of the art and and zoom in on new technologies that will provide the tools necessary to investigate host-parasite interactions of relapsing parasites. Interactions between hypnozoites and hepatocytes are particularly interesting because the parasite can remain in a quiescent state for prolonged periods of time and triggers for reactivation have not been irrefutably identified. If we learn more about the cross-talk between hypnozoite and host we may be able to identify factors that encourage waking up these dormant parasite reservoirs and help to achieve the total eradication of malaria.
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Affiliation(s)
| | - Clemens H M Kocken
- Department of Parasitology, Biomedical Primate Research Center, Rijswijk, Netherlands
| | - Anne-Marie Zeeman
- Department of Parasitology, Biomedical Primate Research Center, Rijswijk, Netherlands
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17
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Chloroquine Potentiates Primaquine Activity against Active and Latent Hepatic Plasmodia Ex Vivo: Potentials and Pitfalls. Antimicrob Agents Chemother 2020; 65:AAC.01416-20. [PMID: 33077656 PMCID: PMC7927800 DOI: 10.1128/aac.01416-20] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Accepted: 10/12/2020] [Indexed: 01/05/2023] Open
Abstract
For a long while, 8-aminoquinoline compounds have been the only therapeutic agents against latent hepatic malaria parasites. These have poor activity against the blood-stage plasmodia causing acute malaria and must be used in conjunction with partner blood schizontocidal agents. We examined the impacts of one such agent, chloroquine, upon the activity of primaquine, an 8-aminoquinoline, against hepatic stages of Plasmodium cynomolgi, Plasmodium yoelii, Plasmodium berghei, and Plasmodium falciparum within several ex vivo systems—primary hepatocytes of Macaca fascicularis, primary human hepatocytes, and stably transformed human hepatocarcinoma cell line HepG2. For a long while, 8-aminoquinoline compounds have been the only therapeutic agents against latent hepatic malaria parasites. These have poor activity against the blood-stage plasmodia causing acute malaria and must be used in conjunction with partner blood schizontocidal agents. We examined the impacts of one such agent, chloroquine, upon the activity of primaquine, an 8-aminoquinoline, against hepatic stages of Plasmodium cynomolgi, Plasmodium yoelii, Plasmodium berghei, and Plasmodium falciparum within several ex vivo systems—primary hepatocytes of Macaca fascicularis, primary human hepatocytes, and stably transformed human hepatocarcinoma cell line HepG2. Primaquine exposures to formed hepatic schizonts and hypnozoites of P. cynomolgi in primary simian hepatocytes exhibited similar 50% inhibitory concentration (IC50) values near 0.4 μM, whereas chloroquine in the same system exhibited no inhibitory activities. Combining chloroquine and primaquine in this system decreased the observed primaquine IC50 for all parasite forms in a chloroquine dose-dependent manner by an average of 18-fold. Chloroquine also decreased the primaquine IC50 against hepatic P. falciparum in primary human hepatocytes, P. berghei in simian primary hepatocytes, and P. yoelii in primary human hepatocytes. Chloroquine had no impact on primaquine IC50 against P. yoelii in HepG2 cells and, likewise, had no impact on the IC50 of atovaquone (hepatic schizontocide) against P. falciparum in human hepatocytes. We describe important sources of variability in the potentiation of primaquine activity by chloroquine in these systems. Chloroquine potentiated primaquine activity against hepatic forms of several plasmodia. We conclude that chloroquine specifically potentiated 8-aminoquinoline activities against active and dormant hepatic-stage plasmodia in normal primary hepatocytes but not in a hepatocarcinoma cell line.
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18
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Gupta DK, Diagana T. In vitro Cultivation and Visualization of Malaria Liver Stages in Primary Simian Hepatocytes. Bio Protoc 2020; 10:e3722. [PMID: 33659384 PMCID: PMC7842340 DOI: 10.21769/bioprotoc.3722] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 05/20/2020] [Accepted: 06/29/2020] [Indexed: 08/25/2024] Open
Abstract
Human liver is the primary and obligatory site for malaria infection where sporozoites invade host hepatocytes. Malaria hepatic stages are asymptomatic and represent an attractive target for development of anti-malarial interventions and vaccines. However, owing to lack of robust and reproducible in vitro culture system, it is difficult to target and study this imperative malaria liver stage. Here, we describe a procedure that allow cultivation and visualization of malaria hepatic stages including dormant hypnozoites using primary simian hepatocytes. This method enables sensitive and quantitative assessment of different hepatic stages in vitro.
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Affiliation(s)
- Devendra Kumar Gupta
- Novartis Institute for Tropical Diseases, 5300 Chiron way, Emeryville, California 94608, United States
| | - Thierry Diagana
- Novartis Institute for Tropical Diseases, 5300 Chiron way, Emeryville, California 94608, United States
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19
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Kublin JG, Murphy SC, Maenza J, Seilie AM, Jain JP, Berger D, Spera D, Zhao R, Soon RL, Czartoski JL, Potochnic MA, Duke E, Chang M, Vaughan A, Kappe SHI, Leong FJ, Pertel P, Prince WT. Safety, pharmacokinetics and causal prophylactic efficacy of KAF156 in a Plasmodium falciparum human infection study. Clin Infect Dis 2020; 73:e2407-e2414. [PMID: 32644127 DOI: 10.1093/cid/ciaa952] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 07/07/2020] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND KAF156 is a novel antimalarial drug that is active against both liver- and blood- stage Plasmodium parasites, including drug-resistant strains. Here, we investigated the causal prophylactic efficacy of KAF156 in a controlled human malaria infection (CHMI) model. METHODS In Part 1, healthy, malaria-naïve participants received 800 mg KAF156 or placebo three hr before CHMI with Pf-infected mosquitoes. In Part 2, KAF156 was administered as single doses of 800, 300, 100, 50, or 20 mg 21 hr post-CHMI. All participants received atovaquone/proguanil treatment if blood-stage infection was detected or on day 29. For each cohort, 7-14 subjects were enrolled to KAF156 treatment and up to four subjects to placebo. RESULTS KAF156 at all dose levels was safe and well tolerated. Two serious adverse events were reported - both resolved without sequelae and neither was considered related to KAF156. In Part 1, all participants treated with KAF156 and none of those randomized to placebo were protected against malaria infection. In Part 2, all participants treated with placebo or 20 mg KAF156 developed malaria infection. In contrast, 50 mg KAF156 protected 3/14 participants from infection, and doses of 800, 300, and 100 mg KAF156 protected all subjects against infection. An exposure-response analysis suggested that a 24-hr post-dose concentration of KAF156 of 21·5 ng/mL (90% CI 17.66 to 25.32 ng/mL) would ensure a 95% chance of protection from malaria parasite infection. CONCLUSIONS KAF156 was safe and well tolerated and demonstrated high levels of pre- and post-CHMI protective efficacy.
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Affiliation(s)
- James G Kublin
- Seattle Malaria Clinical Trials Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,Departments of Laboratory Medicine and Microbiology and the Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, Washington, USA
| | - Sean C Murphy
- Departments of Laboratory Medicine and Microbiology and the Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, Washington, USA
| | - Janine Maenza
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Annette M Seilie
- Departments of Laboratory Medicine and Microbiology and the Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, Washington, USA
| | - Jay Prakash Jain
- Novartis Institutes for BioMedical Research, Emeryville, California, USA.,Novartis Healthcare Pvt Ltd, Salarpuria-Sattva Knowledge City Raidurg, Rangareddy District Madhapur/ Hyderabad, Rangareddy, India
| | - David Berger
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Danielle Spera
- Novartis Institutes for BioMedical Research, Emeryville, California, USA
| | - Rong Zhao
- Novartis Institutes for BioMedical Research, Emeryville, California, USA
| | - Rachel L Soon
- Novartis Pharmaceuticals, Health Plaza, East Hanover, NJ
| | - Julie L Czartoski
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | | | - Elizabeth Duke
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Ming Chang
- Departments of Laboratory Medicine and Microbiology and the Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, Washington, USA
| | - Ashley Vaughan
- Seattle Children's Research Institute, Seattle, Washington, USA
| | | | - F Joel Leong
- Novartis Institutes for BioMedical Research, Emeryville, California, USA
| | - Peter Pertel
- Novartis Institutes for BioMedical Research, Emeryville, California, USA
| | - William T Prince
- Novartis Institutes for BioMedical Research, Emeryville, California, USA
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20
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Voorberg-van der Wel A, Zeeman AM, Nieuwenhuis IG, van der Werff NM, Klooster EJ, Klop O, Vermaat LC, Kocken CHM. Dual-Luciferase-Based Fast and Sensitive Detection of Malaria Hypnozoites for the Discovery of Antirelapse Compounds. Anal Chem 2020; 92:6667-6675. [PMID: 32267675 PMCID: PMC7203758 DOI: 10.1021/acs.analchem.0c00547] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 04/08/2020] [Indexed: 01/24/2023]
Abstract
Efforts to eradicate Plasmodium vivax malaria are hampered by the presence of hypnozoites, persisting stages in the liver that can reactivate after prolonged periods of time enabling further transmission and causing renewed disease. Large-scale drug screening is needed to identify compounds with antihypnozoite activity, but current platforms rely on time-consuming high-content fluorescence imaging as read-out, limiting assay throughput. We here report an ultrafast and sensitive dual-luciferase-based method to differentiate hypnozoites from liver stage schizonts using a transgenic P. cynomolgi parasite line that contains Nanoluc driven by the constitutive hsp70 promoter, as well as firefly luciferase driven by the schizont-specific lisp2 promoter. The transgenic parasite line showed similar fitness and drug sensitivity profiles of selected compounds to wild type. We demonstrate robust bioluminescence-based detection of hypnozoites in 96-well and 384-well plate formats, setting the stage for implementation in large scale drug screens.
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Affiliation(s)
| | - Anne-Marie Zeeman
- Department of Parasitology, Biomedical Primate Research Centre, 2288 GJ Rijswijk, The Netherlands
| | - Ivonne G. Nieuwenhuis
- Department of Parasitology, Biomedical Primate Research Centre, 2288 GJ Rijswijk, The Netherlands
| | - Nicole M. van der Werff
- Department of Parasitology, Biomedical Primate Research Centre, 2288 GJ Rijswijk, The Netherlands
| | - Els J. Klooster
- Department of Parasitology, Biomedical Primate Research Centre, 2288 GJ Rijswijk, The Netherlands
| | - Onny Klop
- Department of Parasitology, Biomedical Primate Research Centre, 2288 GJ Rijswijk, The Netherlands
| | - Lars C. Vermaat
- Department of Parasitology, Biomedical Primate Research Centre, 2288 GJ Rijswijk, The Netherlands
| | - Clemens H. M. Kocken
- Department of Parasitology, Biomedical Primate Research Centre, 2288 GJ Rijswijk, The Netherlands
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21
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Kawai S, Annoura T, Araki T, Shiogama Y, Soma S, Takano JI, Sato MO, Kaneko O, Yasutomi Y, Chigusa Y. Development of an effective alternative model for in vivo hypnozoite-induced relapse infection: A Japanese macaque (Macaca fuscata) model experimentally infected with Plasmodium cynomolgi. Parasitol Int 2020; 76:102096. [PMID: 32114084 DOI: 10.1016/j.parint.2020.102096] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Revised: 02/22/2020] [Accepted: 02/25/2020] [Indexed: 10/24/2022]
Abstract
In the present study, we demonstrate that the Japanese macaque (Macaca fuscata) can be used as an effective alternative in vivo model for investigating hypnozoite-induced relapsing infection caused by Plasmodium cynomolgi B strain, and that this model is comparable to the rhesus macaque model. Two female Japanese macaques (JM-1 and JM-2; aged 5 years; weighing about 4.0 kg) were used for the experiment. To produce sporozoites in mosquitoes, blood infected with P. cynomolgi B strain was collected from the donor monkey JM-1 and fed to approximately 200 mosquitoes using the standard artificial membrane feeding method. The isolated sporozoites (2 × 105) were intravenously inoculated into the JM-2 monkey, and the blood stage of the parasite was detected on day 8 after the infection. Chloroquine sulfate (CQ) was intramuscularly administered at a dosage of 6.0 mg/kg into the JM-2 monkey for 6 consecutive days from day 12 onward, after which the parasites disappeared from the peripheral blood. The first relapse occurred on day 26, which was treated again with CQ. Then, the second relapse occurred on day 44, which was cured by CQ treatment followed by the administration of primaquine phosphate (PQ) at a dosage of 1.0 mg/kg/day for 15 days. The JM-2 monkey was observed until 69 days after PQ administration, and there was no relapse during the entire follow-up period. We propose that the Japanese macaque model could contribute not only to drug screening for anti-hypnozoite activity, but could also be used as a powerful tool for investigating hypnozoite biology.
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Affiliation(s)
- Satoru Kawai
- Department of Tropical Medicine and Parasitology, Dokkyo Medical University, Mibu, Tochigi, Japan.
| | - Takeshi Annoura
- Department of Parasitology, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, Japan
| | - Tamasa Araki
- Department of Parasitology, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, Japan; Graduate School of Life and Environmental Sciences, University of Tsukuba, Ibaraki, Japan
| | - Yumiko Shiogama
- Laboratory of Immunoregulation and Vaccine Research, Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Health and Nutrition, Tsukuba, Ibaraki, Japan
| | - Shogo Soma
- Laboratory of Immunoregulation and Vaccine Research, Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Health and Nutrition, Tsukuba, Ibaraki, Japan
| | - Jun-Ichiro Takano
- Laboratory of Immunoregulation and Vaccine Research, Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Health and Nutrition, Tsukuba, Ibaraki, Japan
| | - Marcello Otake Sato
- Department of Tropical Medicine and Parasitology, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Osamu Kaneko
- Department of Protozoology, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan
| | - Yasuhiro Yasutomi
- Laboratory of Immunoregulation and Vaccine Research, Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Health and Nutrition, Tsukuba, Ibaraki, Japan
| | - Yuichi Chigusa
- Department of Tropical Medicine and Parasitology, Dokkyo Medical University, Mibu, Tochigi, Japan
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22
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Discovery of 6′-chloro-N-methyl-5’-(phenylsulfonamido)-[3,3′-bipyridine]-5-carboxamide (CHMFL-PI4K-127) as a novel Plasmodium falciparum PI(4)K inhibitor with potent antimalarial activity against both blood and liver stages of Plasmodium. Eur J Med Chem 2020; 188:112012. [DOI: 10.1016/j.ejmech.2019.112012] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 12/21/2019] [Accepted: 12/25/2019] [Indexed: 11/20/2022]
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23
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A dual fluorescent Plasmodium cynomolgi reporter line reveals in vitro malaria hypnozoite reactivation. Commun Biol 2020; 3:7. [PMID: 31909199 PMCID: PMC6941962 DOI: 10.1038/s42003-019-0737-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 12/12/2019] [Indexed: 12/21/2022] Open
Abstract
Plasmodium vivax malaria is characterized by repeated episodes of blood stage infection (relapses) resulting from activation of dormant stages in the liver, so-called hypnozoites. Transition of hypnozoites into developing schizonts has never been observed. A barrier for studying this has been the lack of a system in which to monitor growth of liver stages. Here, exploiting the unique strengths of the simian hypnozoite model P. cynomolgi, we have developed green-fluorescent (GFP) hypnozoites that turn on red-fluorescent (mCherry) upon activation. The transgenic parasites show full liver stage development, including merozoite release and red blood cell infection. We demonstrate that individual hypnozoites actually can activate and resume development after prolonged culture, providing the last missing evidence of the hypnozoite theory of relapse. The few events identified indicate that hypnozoite activation in vitro is infrequent. This system will further our understanding of the mechanisms of hypnozoite activation and may facilitate drug discovery approaches.
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24
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Mellin R, Boddey JA. Organoids for Liver Stage Malaria Research. Trends Parasitol 2019; 36:158-169. [PMID: 31848118 DOI: 10.1016/j.pt.2019.12.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 12/02/2019] [Accepted: 12/02/2019] [Indexed: 11/30/2022]
Abstract
Plasmodium parasites cause malaria and are maintained between Anopheles mosquitoes and mammalian hosts in a complex life cycle. Malaria parasites occupy tissue niches that can be difficult to access, and models to study them can be challenging to recapitulate experimentally, particularly for Plasmodium species that infect humans. 2D culture models provide extremely beneficial tools to investigate Plasmodium biology but they have limitations. More complex 3D structural networks, such as organoids, have unveiled new avenues for developing more physiological tissue models, and their application to malaria research offers great promise. Here, we review current models for studying Plasmodium infection with a key focus on the obligate pre-erythrocytic stage that culminates in blood infection, causing malaria, and discuss how organoids should fulfil an important and unmet need.
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Affiliation(s)
- Ronan Mellin
- The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Victoria, Australia
| | - Justin A Boddey
- The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Victoria, Australia.
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25
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Chua ACY, Ong JJY, Malleret B, Suwanarusk R, Kosaisavee V, Zeeman AM, Cooper CA, Tan KSW, Zhang R, Tan BH, Abas SN, Yip A, Elliot A, Joyner CJ, Cho JS, Breyer K, Baran S, Lange A, Maher SP, Nosten F, Bodenreider C, Yeung BKS, Mazier D, Galinski MR, Dereuddre-Bosquet N, Le Grand R, Kocken CHM, Rénia L, Kyle DE, Diagana TT, Snounou G, Russell B, Bifani P. Robust continuous in vitro culture of the Plasmodium cynomolgi erythrocytic stages. Nat Commun 2019; 10:3635. [PMID: 31406175 PMCID: PMC6690977 DOI: 10.1038/s41467-019-11332-4] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 06/28/2019] [Indexed: 01/19/2023] Open
Abstract
The ability to culture pathogenic organisms substantially enhances the quest for fundamental knowledge and the development of vaccines and drugs. Thus, the elaboration of a protocol for the in vitro cultivation of the erythrocytic stages of Plasmodium falciparum revolutionized research on this important parasite. However, for P. vivax, the most widely distributed and difficult to treat malaria parasite, a strict preference for reticulocytes thwarts efforts to maintain it in vitro. Cultivation of P. cynomolgi, a macaque-infecting species phylogenetically close to P. vivax, was briefly reported in the early 1980s, but not pursued further. Here, we define the conditions under which P. cynomolgi can be adapted to long term in vitro culture to yield parasites that share many of the morphological and phenotypic features of P. vivax. We further validate the potential of this culture system for high-throughput screening to prime and accelerate anti-P. vivax drug discovery efforts. Present understanding of Plasmodium vivax biology is hampered by its inability to grow in vitro. Here, the authors developed an in vitro culture of its simian counterpart, P. cynomolgi, which shares morphological and phenotypic similarities with P. vivax, initiating a new phase in vivax research.
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Affiliation(s)
- Adeline C Y Chua
- Singapore Immunology Network, A*STAR, Singapore, 138648, Singapore.,Department of Microbiology and Immunology, University of Otago, Dunedin, 9054, New Zealand.,Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore
| | - Jessica Jie Ying Ong
- Department of Microbiology and Immunology, University of Otago, Dunedin, 9054, New Zealand.,Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore
| | - Benoit Malleret
- Singapore Immunology Network, A*STAR, Singapore, 138648, Singapore.,Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119077, Singapore
| | - Rossarin Suwanarusk
- Singapore Immunology Network, A*STAR, Singapore, 138648, Singapore.,Department of Microbiology and Immunology, University of Otago, Dunedin, 9054, New Zealand
| | - Varakorn Kosaisavee
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119077, Singapore.,Department of Parasitology and Entomology, Faculty of Public Health, Mahidol University, Bangkok, 10400, Thailand
| | - Anne-Marie Zeeman
- Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, 2288, The Netherlands
| | - Caitlin A Cooper
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, 30602, USA
| | - Kevin S W Tan
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119077, Singapore
| | - Rou Zhang
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119077, Singapore
| | - Bee Huat Tan
- Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore
| | | | - Andy Yip
- Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore
| | - Anne Elliot
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, 30602, USA
| | - Chester J Joyner
- Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, Emory University, Atlanta, 30322, USA.,Emory Vaccine Center, Emory University, Atlanta, 30317, USA
| | - Jee Sun Cho
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119077, Singapore
| | - Kate Breyer
- Laboratory Animal Services, Scientific Operations, Novartis Institutes for Biomedical Research, East Hanover, 07936-1080, USA
| | - Szczepan Baran
- Laboratory Animal Services, Scientific Operations, Novartis Institutes for Biomedical Research, East Hanover, 07936-1080, USA
| | - Amber Lange
- Laboratory Animal Services, Scientific Operations, Novartis Institutes for Biomedical Research, East Hanover, 07936-1080, USA
| | - Steven P Maher
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, 30602, USA
| | - François Nosten
- Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, 63110, Thailand.,Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine Research Building, University of Oxford Old Road Campus, Oxford, OX3 7FZ, UK
| | | | - Bryan K S Yeung
- Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore
| | - Dominique Mazier
- Sorbonne Universités, UPMC Univ Paris 06, CR7, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, F-75013, France.,CIMI-Paris, INSERM, U1135, CNRS, Paris, F-75013, France
| | - Mary R Galinski
- Emory Vaccine Center, Emory University, Atlanta, 30317, USA.,Division of Infectious Diseases, Department of Medicine, Emory University, Atlanta, 30322, USA
| | - Nathalie Dereuddre-Bosquet
- CEA-Université Paris Sud 11-INSERM U1184, Immunology of Viral Infections and Autoimmune Diseases (IMVA), IDMIT Department, IBJF, DRF, Fontenay-aux-Roses, 92265, France
| | - Roger Le Grand
- CEA-Université Paris Sud 11-INSERM U1184, Immunology of Viral Infections and Autoimmune Diseases (IMVA), IDMIT Department, IBJF, DRF, Fontenay-aux-Roses, 92265, France
| | - Clemens H M Kocken
- Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, 2288, The Netherlands
| | - Laurent Rénia
- Singapore Immunology Network, A*STAR, Singapore, 138648, Singapore.,Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119077, Singapore
| | - Dennis E Kyle
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, 30602, USA
| | - Thierry T Diagana
- Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore
| | - Georges Snounou
- Sorbonne Universités, UPMC Univ Paris 06, CR7, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, F-75013, France.,CIMI-Paris, INSERM, U1135, CNRS, Paris, F-75013, France.,CEA-Université Paris Sud 11-INSERM U1184, Immunology of Viral Infections and Autoimmune Diseases (IMVA), IDMIT Department, IBJF, DRF, Fontenay-aux-Roses, 92265, France
| | - Bruce Russell
- Department of Microbiology and Immunology, University of Otago, Dunedin, 9054, New Zealand.
| | - Pablo Bifani
- Singapore Immunology Network, A*STAR, Singapore, 138648, Singapore. .,Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore. .,Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119077, Singapore. .,Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, WC1E 7HT, UK.
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26
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Chua ACY, Ananthanarayanan A, Ong JJY, Wong JY, Yip A, Singh NH, Qu Y, Dembele L, McMillian M, Ubalee R, Davidson S, Tungtaeng A, Imerbsin R, Gupta K, Andolina C, Lee F, S-W Tan K, Nosten F, Russell B, Lange A, Diagana TT, Rénia L, Yeung BKS, Yu H, Bifani P. Hepatic spheroids used as an in vitro model to study malaria relapse. Biomaterials 2019; 216:119221. [PMID: 31195301 DOI: 10.1016/j.biomaterials.2019.05.032] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 05/19/2019] [Indexed: 12/27/2022]
Abstract
Hypnozoites are the liver stage non-dividing form of the malaria parasite that are responsible for relapse and acts as a natural reservoir for human malaria Plasmodium vivax and P. ovale as well as a phylogenetically related simian malaria P. cynomolgi. Our understanding of hypnozoite biology remains limited due to the technical challenge of requiring the use of primary hepatocytes and the lack of robust and predictive in vitro models. In this study, we developed a malaria liver stage model using 3D spheroid-cultured primary hepatocytes. The infection of primary hepatocytes in suspension led to increased infectivity of both P. cynomolgi and P. vivax infections. We demonstrated that this hepatic spheroid model was capable of maintaining long term viability, hepatocyte specific functions and cell polarity which enhanced permissiveness and thus, permitting for the complete development of both P. cynomolgi and P. vivax liver stage parasites in the infected spheroids. The model described here was able to capture the full liver stage cycle starting with sporozoites and ending in the release of hepatic merozoites capable of invading simian erythrocytes in vitro. Finally, we showed that this system can be used for compound screening to discriminate between causal prophylactic and cidal antimalarials activity in vitro for relapsing malaria.
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Affiliation(s)
- Adeline C Y Chua
- Novartis Institute for Tropical Diseases, 138670, Singapore; Department of Microbiology and Immunology, University of Otago, Dunedin 9054, New Zealand; Singapore Immunology Network (SIgN), A*STAR, 138648, Singapore
| | | | - Jessica Jie Ying Ong
- Novartis Institute for Tropical Diseases, 138670, Singapore; Department of Microbiology and Immunology, University of Otago, Dunedin 9054, New Zealand
| | | | - Andy Yip
- Novartis Institute for Tropical Diseases, 138670, Singapore
| | | | | | - Laurent Dembele
- Novartis Institute for Tropical Diseases, 138670, Singapore; Université des Sciences, des Techniques et des Technologies de Bamako (USTTB); MRTC - DEAP - Faculty of Pharmacy, Bamako, Mali
| | - Michael McMillian
- Invitrocue Pte Ltd. 138667, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University Health System, 117597, Singapore
| | - Ratawan Ubalee
- Department of Entomology, Armed Forces Research Institute of Medical Science (AFRIMS), Bangkok 10400,Thailand
| | - Silas Davidson
- Department of Entomology, Armed Forces Research Institute of Medical Science (AFRIMS), Bangkok 10400,Thailand
| | - Anchalee Tungtaeng
- Department of Veterinary Medicine, Armed Forces Research Institute of Medical Science (AFRIMS), Bangkok 10400,Thailand
| | - Rawiwan Imerbsin
- Department of Veterinary Medicine, Armed Forces Research Institute of Medical Science (AFRIMS), Bangkok 10400,Thailand
| | - Kapish Gupta
- Mechanobiology Institute, National University of Singapore, 117411, Singapore
| | - Chiara Andolina
- Shoklo Malaria Research Unit (SMRU), Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Fan Lee
- Institute of Bioengineering and Nanotechnology, A*STAR, 138669, Singapore
| | - Kevin S-W Tan
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 119077, Singapore
| | - François Nosten
- Shoklo Malaria Research Unit (SMRU), Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Bruce Russell
- Department of Microbiology and Immunology, University of Otago, Dunedin 9054, New Zealand
| | - Amber Lange
- Laboratory Animal Services, Scientific Operations, Novartis Institutes for Biomedical Research, East Hanover, NJ, 07936-1080, USA
| | | | - Laurent Rénia
- Singapore Immunology Network (SIgN), A*STAR, 138648, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 119077, Singapore
| | | | - Hanry Yu
- Invitrocue Pte Ltd. 138667, Singapore; Mechanobiology Institute, National University of Singapore, 117411, Singapore; Institute of Bioengineering and Nanotechnology, A*STAR, 138669, Singapore
| | - Pablo Bifani
- Novartis Institute for Tropical Diseases, 138670, Singapore; Singapore Immunology Network (SIgN), A*STAR, 138648, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 119077, Singapore.
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27
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Gupta DK, Dembele L, Voorberg-van der Wel A, Roma G, Yip A, Chuenchob V, Kangwanrangsan N, Ishino T, Vaughan AM, Kappe SH, Flannery EL, Sattabongkot J, Mikolajczak S, Bifani P, Kocken CH, Diagana TT. The Plasmodium liver-specific protein 2 (LISP2) is an early marker of liver stage development. eLife 2019; 8:43362. [PMID: 31094679 PMCID: PMC6542585 DOI: 10.7554/elife.43362] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Accepted: 05/13/2019] [Indexed: 02/06/2023] Open
Abstract
Plasmodium vivax hypnozoites persist in the liver, cause malaria relapse and represent a major challenge to malaria elimination. Our previous transcriptomic study provided a novel molecular framework to enhance our understanding of the hypnozoite biology (Voorberg-van der Wel A, et al., 2017). In this dataset, we identified and characterized the Liver-Specific Protein 2 (LISP2) protein as an early molecular marker of liver stage development. Immunofluorescence analysis of hepatocytes infected with relapsing malaria parasites, in vitro (P. cynomolgi) and in vivo (P. vivax), reveals that LISP2 expression discriminates between dormant hypnozoites and early developing parasites. We further demonstrate that prophylactic drugs selectively kill all LISP2-positive parasites, while LISP2-negative hypnozoites are only sensitive to anti-relapse drug tafenoquine. Our results provide novel biological insights in the initiation of liver stage schizogony and an early marker suitable for the development of drug discovery assays predictive of anti-relapse activity.
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Affiliation(s)
- Devendra Kumar Gupta
- Novartis Institute for Tropical Diseases, Emeryville, United States.,Novartis Institute for Tropical Diseases, Singapore, Singapore
| | - Laurent Dembele
- Novartis Institute for Tropical Diseases, Singapore, Singapore.,Faculty of Pharmacy, Université des Sciences, des Techniques et des Technologies de Bamako (USTTB), MRTC - DEAP, Bamako, Mali
| | | | - Guglielmo Roma
- Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Andy Yip
- Novartis Institute for Tropical Diseases, Singapore, Singapore
| | | | | | - Tomoko Ishino
- Graduate School of Medicine, Ehime University, Toon, Japan
| | | | - Stefan H Kappe
- Center for Infectious Disease Research, Seattle, United States
| | | | | | - Sebastian Mikolajczak
- Novartis Institute for Tropical Diseases, Emeryville, United States.,Center for Infectious Disease Research, Seattle, United States
| | - Pablo Bifani
- Novartis Institute for Tropical Diseases, Singapore, Singapore.,Singapore Immunology Network (SIgN), Singapore, Singapore.,Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Clemens Hm Kocken
- Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, Netherlands
| | - Thierry Tidiane Diagana
- Novartis Institute for Tropical Diseases, Emeryville, United States.,Novartis Institute for Tropical Diseases, Singapore, Singapore
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28
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Yahiya S, Rueda-Zubiaurre A, Delves MJ, Fuchter MJ, Baum J. The antimalarial screening landscape-looking beyond the asexual blood stage. Curr Opin Chem Biol 2019; 50:1-9. [PMID: 30875617 PMCID: PMC6591700 DOI: 10.1016/j.cbpa.2019.01.029] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 01/28/2019] [Accepted: 01/30/2019] [Indexed: 12/20/2022]
Abstract
In recent years, the research agenda to tackle global morbidity and mortality from malaria disease has shifted towards innovation, in the hope that efforts at the frontiers of scientific research may re-invigorate gains made towards eradication. Discovery of new antimalarial drugs with novel chemotypes or modes of action lie at the heart of these efforts. There is a particular interest in drug candidates that target stages of the malaria parasite lifecycle beyond the symptomatic asexual blood stages. This is especially important given the spectre of emerging drug resistance to all current frontline antimalarials. One approach gaining increased interest is the potential of designing novel drugs that target parasite passage from infected individual to feeding mosquito and back again. Action of such therapeutics is geared much more at the population level rather than just concerned with the infected individual. The search for novel drugs active against these stages has been helped by improvements to in vitro culture of transmission and pre-erythrocytic parasite lifecycle stages, robotic automation and high content imaging, methodologies that permit the high-throughput screening (HTS) of compound libraries for drug discovery. Here, we review recent advances in the antimalarial screening landscape, focussed on transmission blocking as a key aim for drug-treatment campaigns of the future.
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Affiliation(s)
- Sabrina Yahiya
- Department of Life Sciences, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, UK
| | - Ainoa Rueda-Zubiaurre
- Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, Wood Lane, London W12 OBZ, UK
| | - Michael J Delves
- London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK
| | - Matthew J Fuchter
- Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, Wood Lane, London W12 OBZ, UK
| | - Jake Baum
- Department of Life Sciences, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, UK.
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29
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Bertschi NL, Voorberg-van der Wel A, Zeeman AM, Schuierer S, Nigsch F, Carbone W, Knehr J, Gupta DK, Hofman SO, van der Werff N, Nieuwenhuis I, Klooster E, Faber BW, Flannery EL, Mikolajczak SA, Chuenchob V, Shrestha B, Beibel M, Bouwmeester T, Kangwanrangsan N, Sattabongkot J, Diagana TT, Kocken CH, Roma G. Transcriptomic analysis reveals reduced transcriptional activity in the malaria parasite Plasmodium cynomolgi during progression into dormancy. eLife 2018; 7:41081. [PMID: 30589413 PMCID: PMC6344078 DOI: 10.7554/elife.41081] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 12/23/2018] [Indexed: 02/06/2023] Open
Abstract
Relapses of Plasmodium dormant liver hypnozoites compromise malaria eradication efforts. New radical cure drugs are urgently needed, yet the vast gap in knowledge of hypnozoite biology impedes drug discovery. We previously unraveled the transcriptome of 6 to 7 day-old P. cynomolgi liver stages, highlighting pathways associated with hypnozoite dormancy (Voorberg-van der Wel et al., 2017). We now extend these findings by transcriptome profiling of 9 to 10 day-old liver stage parasites, thus revealing for the first time the maturation of the dormant stage over time. Although progression of dormancy leads to a 10-fold decrease in transcription and expression of only 840 genes, including genes associated with housekeeping functions, we show that pathways involved in quiescence, energy metabolism and maintenance of genome integrity remain the prevalent pathways active in mature hypnozoites.
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Affiliation(s)
- Nicole L Bertschi
- Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Europe
| | | | - Anne-Marie Zeeman
- Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, The Netherlands
| | - Sven Schuierer
- Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Europe
| | - Florian Nigsch
- Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Europe
| | - Walter Carbone
- Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Europe
| | - Judith Knehr
- Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Europe
| | - Devendra K Gupta
- Novartis Institute for Tropical Diseases, Novartis Pharma AG, Emeryville, United States
| | - Sam O Hofman
- Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, The Netherlands
| | - Nicole van der Werff
- Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, The Netherlands
| | - Ivonne Nieuwenhuis
- Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, The Netherlands
| | - Els Klooster
- Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, The Netherlands
| | - Bart W Faber
- Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, The Netherlands
| | - Erika L Flannery
- Novartis Institute for Tropical Diseases, Novartis Pharma AG, Emeryville, United States
| | | | - Vorada Chuenchob
- Novartis Institute for Tropical Diseases, Novartis Pharma AG, Emeryville, United States
| | - Binesh Shrestha
- Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Europe
| | - Martin Beibel
- Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Europe
| | - Tewis Bouwmeester
- Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Europe
| | - Niwat Kangwanrangsan
- Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Jetsumon Sattabongkot
- Mahidol Vivax Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Thierry T Diagana
- Novartis Institute for Tropical Diseases, Novartis Pharma AG, Emeryville, United States
| | - Clemens Hm Kocken
- Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, The Netherlands
| | - Guglielmo Roma
- Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Europe
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30
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UCT943, a Next-Generation Plasmodium falciparum PI4K Inhibitor Preclinical Candidate for the Treatment of Malaria. Antimicrob Agents Chemother 2018; 62:AAC.00012-18. [PMID: 29941635 PMCID: PMC6125526 DOI: 10.1128/aac.00012-18] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 06/07/2018] [Indexed: 01/12/2023] Open
Abstract
The 2-aminopyridine MMV048 was the first drug candidate inhibiting Plasmodium phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite life cycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver stage activities than MMV048 and was more potent against resistant Plasmodium falciparum and Plasmodium vivax clinical isolates. Excellent in vitro antiplasmodial activity translated into high efficacy in Plasmodium berghei and humanized P. falciparum NOD-scid IL-2Rγ null mouse models. The high passive permeability and high aqueous solubility of UCT943, combined with low to moderate in vivo intrinsic clearance, resulted in sustained exposure and high bioavailability in preclinical species. In addition, the predicted human dose for a curative single administration using monkey and dog pharmacokinetics was low, ranging from 50 to 80 mg. As a next-generation Plasmodium PI4K inhibitor, UCT943, based on the combined preclinical data, has the potential to form part of a single-exposure radical cure and prophylaxis (SERCaP) to treat, prevent, and block the transmission of malaria.
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31
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Abstract
The last two decades have seen a surge in antimalarial drug development with product development partnerships taking a leading role. Resistance of Plasmodium falciparum to the artemisinin derivatives, piperaquine and mefloquine in Southeast Asia means new antimalarials are needed with some urgency. There are at least 13 agents in clinical development. Most of these are blood schizonticides for the treatment of uncomplicated falciparum malaria, under evaluation either singly or as part of two-drug combinations. Leading candidates progressing through the pipeline are artefenomel-ferroquine and lumefantrine-KAF156, both in Phase 2b. Treatment of severe malaria continues to rely on two parenteral drugs with ancient forebears: artesunate and quinine, with sevuparin being evaluated as an adjuvant therapy. Tafenoquine is under review by stringent regulatory authorities for approval as a single-dose treatment for Plasmodium vivax relapse prevention. This represents an advance over standard 14-day primaquine regimens; however, the risk of acute haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency remains. For disease prevention, several of the newer agents show potential but are unlikely to be recommended for use in the main target groups of pregnant women and young children for some years. Latest predictions are that the malaria burden will continue to be high in the coming decades. This fact, coupled with the repeated loss of antimalarials to resistance, indicates that new antimalarials will be needed for years to come. Failure of the artemisinin-based combinations in Southeast Asia has stimulated a reappraisal of current approaches to combination therapy for malaria with incorporation of three or more drugs in a single treatment under consideration.
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Affiliation(s)
- Elizabeth A Ashley
- Myanmar Oxford Clinical Research Unit, Yangon, Myanmar.
- Nuffield Department of Medicine, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK.
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32
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Paquet T, Le Manach C, Cabrera DG, Younis Y, Henrich PP, Abraham TS, Lee MCS, Basak R, Ghidelli-Disse S, Lafuente-Monasterio MJ, Bantscheff M, Ruecker A, Blagborough AM, Zakutansky SE, Zeeman AM, White KL, Shackleford DM, Mannila J, Morizzi J, Scheurer C, Angulo-Barturen I, Martínez MS, Ferrer S, Sanz LM, Gamo FJ, Reader J, Botha M, Dechering KJ, Sauerwein RW, Tungtaeng A, Vanachayangkul P, Lim CS, Burrows J, Witty MJ, Marsh KC, Bodenreider C, Rochford R, Solapure SM, Jiménez-Díaz MB, Wittlin S, Charman SA, Donini C, Campo B, Birkholtz LM, Hanson KK, Drewes G, Kocken CHM, Delves MJ, Leroy D, Fidock DA, Waterson D, Street LJ, Chibale K. Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase. Sci Transl Med 2018; 9:9/387/eaad9735. [PMID: 28446690 DOI: 10.1126/scitranslmed.aad9735] [Citation(s) in RCA: 189] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Accepted: 11/21/2016] [Indexed: 12/13/2022]
Abstract
As part of the global effort toward malaria eradication, phenotypic whole-cell screening revealed the 2-aminopyridine class of small molecules as a good starting point to develop new antimalarial drugs. Stemming from this series, we found that the derivative, MMV390048, lacked cross-resistance with current drugs used to treat malaria. This compound was efficacious against all Plasmodium life cycle stages, apart from late hypnozoites in the liver. Efficacy was shown in the humanized Plasmodium falciparum mouse model, and modest reductions in mouse-to-mouse transmission were achieved in the Plasmodium berghei mouse model. Experiments in monkeys revealed the ability of MMV390048 to be used for full chemoprotection. Although MMV390048 was not able to eliminate liver hypnozoites, it delayed relapse in a Plasmodium cynomolgi monkey model. Both genomic and chemoproteomic studies identified a kinase of the Plasmodium parasite, phosphatidylinositol 4-kinase, as the molecular target of MMV390048. The ability of MMV390048 to block all life cycle stages of the malaria parasite suggests that this compound should be further developed and may contribute to malaria control and eradication as part of a single-dose combination treatment.
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Affiliation(s)
- Tanya Paquet
- Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
| | - Claire Le Manach
- Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
| | | | - Yassir Younis
- Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
| | - Philipp P Henrich
- Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.,The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - Tara S Abraham
- Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.,Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 1020 Locust Street, Suite 368, Philadelphia, PA 19107, USA
| | - Marcus C S Lee
- Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.,Malaria Programme, Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK
| | - Rajshekhar Basak
- Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.,Department of Molecular Biophysics and Biochemistry, Yale University, 266 Whitney Avenue, New Haven, CT 06520-8114, USA
| | - Sonja Ghidelli-Disse
- Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, 69117 Heidelberg, Germany
| | - María José Lafuente-Monasterio
- Malaria Disease Performance Unit, Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
| | - Marcus Bantscheff
- Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, 69117 Heidelberg, Germany
| | - Andrea Ruecker
- Department of Life Sciences, Imperial College, London SW7 2AZ, UK
| | | | | | - Anne-Marie Zeeman
- Department of Parasitology, Biomedical Primate Research Centre, 2280 GH Rijswijk, Netherlands
| | - Karen L White
- Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
| | - David M Shackleford
- Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
| | - Janne Mannila
- Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.,Admescope Ltd., Typpitie 1, 90620 Oulu, Finland
| | - Julia Morizzi
- Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
| | - Christian Scheurer
- Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland.,University of Basel, 4003 Basel, Switzerland
| | - Iñigo Angulo-Barturen
- Malaria Disease Performance Unit, Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
| | - María Santos Martínez
- Malaria Disease Performance Unit, Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
| | - Santiago Ferrer
- Malaria Disease Performance Unit, Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
| | - Laura María Sanz
- Malaria Disease Performance Unit, Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
| | - Francisco Javier Gamo
- Malaria Disease Performance Unit, Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
| | - Janette Reader
- Department of Biochemistry, Centre for Sustainable Malaria Control, University of Pretoria, Pretoria, South Africa
| | - Mariette Botha
- Department of Biochemistry, Centre for Sustainable Malaria Control, University of Pretoria, Pretoria, South Africa
| | - Koen J Dechering
- TropIQ Health Sciences, Transistorweg 5, 6534 AT Nijmegen, Netherlands
| | - Robert W Sauerwein
- TropIQ Health Sciences, Transistorweg 5, 6534 AT Nijmegen, Netherlands.,Radboud University Medical Center, Department of Medical Microbiology, 6500 HB Nijmegen, Netherlands
| | - Anchalee Tungtaeng
- Department of Veterinary Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok 10400, Thailand
| | - Pattaraporn Vanachayangkul
- Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok 10400, Thailand
| | - Chek Shik Lim
- Novartis Institute for Tropical Diseases Pte. Ltd., 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore
| | - Jeremy Burrows
- Medicines for Malaria Venture, International Center Cointrin, Route de Pré-Bois 20, 1215 Geneva, Switzerland
| | - Michael J Witty
- Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.,Medicines for Malaria Venture, International Center Cointrin, Route de Pré-Bois 20, 1215 Geneva, Switzerland
| | - Kennan C Marsh
- AbbVie, 1 North Waukegan Road, North Chicago, IL 60064-6104, USA
| | - Christophe Bodenreider
- Novartis Institute for Tropical Diseases Pte. Ltd., 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore
| | - Rosemary Rochford
- Departments of Immunology and Microbiology and Environmental and Occupational Health, University of Colorado Denver, Aurora, CO 80045, USA
| | - Suresh M Solapure
- Nagarjuna Gardens, 60 Feet Road, Sahakaranagar, Bangalore 560092, India
| | - María Belén Jiménez-Díaz
- Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 1020 Locust Street, Suite 368, Philadelphia, PA 19107, USA
| | - Sergio Wittlin
- Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland.,University of Basel, 4003 Basel, Switzerland
| | - Susan A Charman
- Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
| | - Cristina Donini
- Medicines for Malaria Venture, International Center Cointrin, Route de Pré-Bois 20, 1215 Geneva, Switzerland
| | - Brice Campo
- Medicines for Malaria Venture, International Center Cointrin, Route de Pré-Bois 20, 1215 Geneva, Switzerland
| | - Lyn-Marie Birkholtz
- Department of Biochemistry, Centre for Sustainable Malaria Control, University of Pretoria, Pretoria, South Africa
| | - Kirsten K Hanson
- Department of Biology and South Texas Center for Emerging Infectious Diseases, University of Texas at San Antonio, 1 UTSA Circle, San Antonio, TX 78249, USA
| | - Gerard Drewes
- Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, 69117 Heidelberg, Germany
| | - Clemens H M Kocken
- Department of Parasitology, Biomedical Primate Research Centre, 2280 GH Rijswijk, Netherlands
| | - Michael J Delves
- Department of Life Sciences, Imperial College, London SW7 2AZ, UK
| | - Didier Leroy
- Medicines for Malaria Venture, International Center Cointrin, Route de Pré-Bois 20, 1215 Geneva, Switzerland
| | - David A Fidock
- Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.,Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
| | - David Waterson
- Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.,Medicines for Malaria Venture, International Center Cointrin, Route de Pré-Bois 20, 1215 Geneva, Switzerland
| | - Leslie J Street
- Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
| | - Kelly Chibale
- Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa. .,South African Medical Research Council Drug Discovery and Development Research Unit, and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa
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33
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Voorberg-van der Wel A, Roma G, Gupta DK, Schuierer S, Nigsch F, Carbone W, Zeeman AM, Lee BH, Hofman SO, Faber BW, Knehr J, Pasini E, Kinzel B, Bifani P, Bonamy GMC, Bouwmeester T, Kocken CHM, Diagana TT. A comparative transcriptomic analysis of replicating and dormant liver stages of the relapsing malaria parasite Plasmodium cynomolgi. eLife 2017; 6:29605. [PMID: 29215331 PMCID: PMC5758109 DOI: 10.7554/elife.29605] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Accepted: 12/05/2017] [Indexed: 01/23/2023] Open
Abstract
Plasmodium liver hypnozoites, which cause disease relapse, are widely considered to be the last barrier towards malaria eradication. The biology of this quiescent form of the parasite is poorly understood which hinders drug discovery. We report a comparative transcriptomic dataset of replicating liver schizonts and dormant hypnozoites of the relapsing parasite Plasmodium cynomolgi. Hypnozoites express only 34% of Plasmodium physiological pathways, while 91% are expressed in replicating schizonts. Few known malaria drug targets are expressed in quiescent parasites, but pathways involved in microbial dormancy, maintenance of genome integrity and ATP homeostasis were robustly expressed. Several transcripts encoding heavy metal transporters were expressed in hypnozoites and the copper chelator neocuproine was cidal to all liver stage parasites. This transcriptomic dataset is a valuable resource for the discovery of vaccines and effective treatments to combat vivax malaria.
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Affiliation(s)
| | - Guglielmo Roma
- Novartis Institutes for BioMedical Research, Basel, Switzerland
| | | | - Sven Schuierer
- Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Florian Nigsch
- Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Walter Carbone
- Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Anne-Marie Zeeman
- Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, Netherlands
| | - Boon Heng Lee
- Novartis Institute for Tropical Diseases, Singapore, Singapore
| | - Sam O Hofman
- Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, Netherlands
| | - Bart W Faber
- Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, Netherlands
| | - Judith Knehr
- Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Erica Pasini
- Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, Netherlands
| | - Bernd Kinzel
- Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Pablo Bifani
- Novartis Institute for Tropical Diseases, Singapore, Singapore
| | | | | | - Clemens H M Kocken
- Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, Netherlands
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34
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The malERA Refresh Consultative Panel on Basic Science and Enabling Technologies. malERA: An updated research agenda for basic science and enabling technologies in malaria elimination and eradication. PLoS Med 2017; 14:e1002451. [PMID: 29190277 PMCID: PMC5708601 DOI: 10.1371/journal.pmed.1002451] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Basic science holds enormous power for revealing the biological mechanisms of disease and, in turn, paving the way toward new, effective interventions. Recognizing this power, the 2011 Research Agenda for Malaria Eradication included key priorities in fundamental research that, if attained, could help accelerate progress toward disease elimination and eradication. The Malaria Eradication Research Agenda (malERA) Consultative Panel on Basic Science and Enabling Technologies reviewed the progress, continuing challenges, and major opportunities for future research. The recommendations come from a literature of published and unpublished materials and the deliberations of the malERA Refresh Consultative Panel. These areas span multiple aspects of the Plasmodium life cycle in both the human host and the Anopheles vector and include critical, unanswered questions about parasite transmission, human infection in the liver, asexual-stage biology, and malaria persistence. We believe an integrated approach encompassing human immunology, parasitology, and entomology, and harnessing new and emerging biomedical technologies offers the best path toward addressing these questions and, ultimately, lowering the worldwide burden of malaria.
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35
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Tufail F, Singh S, Saquib M, Tiwari J, Singh J, Singh J. Catalyst-Free, Glycerol-Assisted Facile Approach to Imidazole-Fused Nitrogen-Bridgehead Heterocycles. ChemistrySelect 2017. [DOI: 10.1002/slct.201700557] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Affiliation(s)
- Fatima Tufail
- Environmentally Benign Synthesis Lab, Department of Chemistry; University of Allahabad; Allahabad- 211002 India
| | - Swastika Singh
- Environmentally Benign Synthesis Lab, Department of Chemistry; University of Allahabad; Allahabad- 211002 India
| | - Mohammad Saquib
- Environmentally Benign Synthesis Lab, Department of Chemistry; University of Allahabad; Allahabad- 211002 India
| | - Jyoti Tiwari
- Environmentally Benign Synthesis Lab, Department of Chemistry; University of Allahabad; Allahabad- 211002 India
| | - Jaya Singh
- Department of Chemistry; LRPG College; Sahibabad, Uttar Pradesh India
| | - Jagdamba Singh
- Environmentally Benign Synthesis Lab, Department of Chemistry; University of Allahabad; Allahabad- 211002 India
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36
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Pasini EM, Böhme U, Rutledge GG, Voorberg-Van der Wel A, Sanders M, Berriman M, Kocken CH, Otto TD. An improved Plasmodium cynomolgi genome assembly reveals an unexpected methyltransferase gene expansion. Wellcome Open Res 2017; 2:42. [PMID: 28748222 PMCID: PMC5500898 DOI: 10.12688/wellcomeopenres.11864.1] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/15/2017] [Indexed: 11/20/2022] Open
Abstract
Background:
Plasmodium cynomolgi, a non-human primate malaria parasite species, has been an important model parasite since its discovery in 1907. Similarities in the biology of
P. cynomolgi to the closely related, but less tractable, human malaria parasite
P. vivax make it the model parasite of choice for liver biology and vaccine studies pertinent to
P. vivax malaria. Molecular and genome-scale studies of
P. cynomolgi have relied on the current reference genome sequence, which remains highly fragmented with 1,649 unassigned scaffolds and little representation of the subtelomeres. Methods: Using long-read sequence data (Pacific Biosciences SMRT technology), we assembled and annotated a new reference genome sequence, PcyM, sourced from an Indian rhesus monkey. We compare the newly assembled genome sequence with those of several other
Plasmodium species, including a re-annotated
P. coatneyi assembly. Results: The new PcyM genome assembly is of significantly higher quality than the existing reference, comprising only 56 pieces, no gaps and an improved average gene length. Detailed manual curation has ensured a comprehensive annotation of the genome with 6,632 genes, nearly 1,000 more than previously attributed to
P. cynomolgi. The new assembly also has an improved representation of the subtelomeric regions, which account for nearly 40% of the sequence. Within the subtelomeres, we identified more than 1300
Plasmodium interspersed repeat (
pir) genes, as well as a striking expansion of 36 methyltransferase pseudogenes that originated from a single copy on chromosome 9. Conclusions: The manually curated PcyM reference genome sequence is an important new resource for the malaria research community. The high quality and contiguity of the data have enabled the discovery of a novel expansion of methyltransferase in the subtelomeres, and illustrates the new comparative genomics capabilities that are being unlocked by complete reference genomes.
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Affiliation(s)
- Erica M Pasini
- Biomedical Primate Research Centre, Rijswijk, Lange Kleiweg 161, 2288GJ Rijswijk, Netherlands
| | - Ulrike Böhme
- The Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
| | - Gavin G Rutledge
- The Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
| | | | - Mandy Sanders
- The Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
| | - Matt Berriman
- The Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
| | - Clemens Hm Kocken
- Biomedical Primate Research Centre, Rijswijk, Lange Kleiweg 161, 2288GJ Rijswijk, Netherlands
| | - Thomas Dan Otto
- The Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
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37
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O'Neill PM, Amewu RK, Charman SA, Sabbani S, Gnädig NF, Straimer J, Fidock DA, Shore ER, Roberts NL, Wong MHL, Hong WD, Pidathala C, Riley C, Murphy B, Aljayyoussi G, Gamo FJ, Sanz L, Rodrigues J, Cortes CG, Herreros E, Angulo-Barturén I, Jiménez-Díaz MB, Bazaga SF, Martínez-Martínez MS, Campo B, Sharma R, Ryan E, Shackleford DM, Campbell S, Smith DA, Wirjanata G, Noviyanti R, Price RN, Marfurt J, Palmer MJ, Copple IM, Mercer AE, Ruecker A, Delves MJ, Sinden RE, Siegl P, Davies J, Rochford R, Kocken CHM, Zeeman AM, Nixon GL, Biagini GA, Ward SA. A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance. Nat Commun 2017; 8:15159. [PMID: 28537265 PMCID: PMC5458052 DOI: 10.1038/ncomms15159] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 03/02/2017] [Indexed: 01/12/2023] Open
Abstract
K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives.
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Affiliation(s)
- Paul M. O'Neill
- Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
- Department of Pharmacology, School of Biomedical Sciences, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE UK
| | - Richard K. Amewu
- Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
| | - Susan A. Charman
- Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
| | - Sunil Sabbani
- Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
| | - Nina F. Gnädig
- Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, HHSC 1502, 701 W. 169th Street, New York, New York 10032, USA
| | - Judith Straimer
- Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, HHSC 1502, 701 W. 169th Street, New York, New York 10032, USA
| | - David A. Fidock
- Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, HHSC 1502, 701 W. 169th Street, New York, New York 10032, USA
- Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, HHSC 1502, 701 W. 168th Street, New York, New York 10032, USA
| | - Emma R. Shore
- Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
| | | | | | - W. David Hong
- Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
| | | | - Chris Riley
- Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
| | - Ben Murphy
- Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
| | - Ghaith Aljayyoussi
- Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK
| | - Francisco Javier Gamo
- Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain
| | - Laura Sanz
- Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain
| | - Janneth Rodrigues
- Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain
| | - Carolina Gonzalez Cortes
- Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain
| | - Esperanza Herreros
- Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain
| | - Iñigo Angulo-Barturén
- Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain
| | - María Belén Jiménez-Díaz
- Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain
| | - Santiago Ferrer Bazaga
- Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain
| | | | - Brice Campo
- Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, Switzerland
| | - Raman Sharma
- Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK
| | - Eileen Ryan
- Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
| | - David M. Shackleford
- Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
| | - Simon Campbell
- Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, Switzerland
| | - Dennis A. Smith
- Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, Switzerland
| | - Grennady Wirjanata
- Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, P.O. Box 41096, Casuarina, Darwin, Northern Territory 0811, Australia
| | - Rintis Noviyanti
- Eijkman Institute for Molecular Biology, Jl. Diponegoro 69, 10430 Jakarta, Indonesia
| | - Ric N. Price
- Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, P.O. Box 41096, Casuarina, Darwin, Northern Territory 0811, Australia
- Nuffield Department of Clinical Medicine, Centre for Tropical Medicine and Global Health, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7FZ, UK
| | - Jutta Marfurt
- Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, P.O. Box 41096, Casuarina, Darwin, Northern Territory 0811, Australia
| | - Michael J. Palmer
- Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, Switzerland
| | - Ian M. Copple
- Department of Pharmacology, School of Biomedical Sciences, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE UK
| | - Amy E. Mercer
- Department of Pharmacology, School of Biomedical Sciences, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE UK
| | - Andrea Ruecker
- Department of Life Sciences, Imperial College London, South Kensington, London SW7 2AZ, UK
| | - Michael J. Delves
- Department of Life Sciences, Imperial College London, South Kensington, London SW7 2AZ, UK
| | - Robert E. Sinden
- Department of Life Sciences, Imperial College London, South Kensington, London SW7 2AZ, UK
- Nuffield Department of Medicine, The Jenner Institute, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK
| | - Peter Siegl
- Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, Switzerland
| | - Jill Davies
- Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK
| | - Rosemary Rochford
- Department of Immunology and Microbiology, University of Colorado, Aurora Colorado, CO 80045, USA
| | - Clemens H. M. Kocken
- Department of Parasitology, Biomedical Primate Research Centre, P. O. Box 3306, 2280 GH Rijswijk, The Netherlands
| | - Anne-Marie Zeeman
- Department of Parasitology, Biomedical Primate Research Centre, P. O. Box 3306, 2280 GH Rijswijk, The Netherlands
| | - Gemma L. Nixon
- Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
| | - Giancarlo A. Biagini
- Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK
| | - Stephen A. Ward
- Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK
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38
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Abstract
The primate malaria Plasmodium knowlesi has a long-standing history as an experimental malaria model. Studies using this model parasite in combination with its various natural and experimental non-human primate hosts have led to important advances in vaccine development and in our understanding of malaria invasion, immunology and parasite-host interactions. The adaptation to long-term in vitro continuous blood stage culture in rhesus monkey, Macaca fascicularis and human red blood cells, as well as the development of various transfection methodologies has resulted in a highly versatile experimental malaria model, further increasing the potential of what was already a very powerful model. The growing evidence that P. knowlesi is an important human zoonosis in South-East Asia has added relevance to former and future studies of this parasite species.
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39
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Phillips MA, White KL, Kokkonda S, Deng X, White J, El Mazouni F, Marsh K, Tomchick DR, Manjalanagara K, Rudra KR, Wirjanata G, Noviyanti R, Price RN, Marfurt J, Shackleford DM, Chiu FC, Campbell M, Jimenez-Diaz MB, Bazaga SF, Angulo-Barturen I, Martinez MS, Lafuente-Monasterio M, Kaminsky W, Silue K, Zeeman AM, Kocken C, Leroy D, Blasco B, Rossignol E, Rueckle T, Matthews D, Burrows JN, Waterson D, Palmer MJ, Rathod PK, Charman SA. A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria. ACS Infect Dis 2016; 2:945-957. [PMID: 27641613 PMCID: PMC5148661 DOI: 10.1021/acsinfecdis.6b00144] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The emergence of drug-resistant malaria parasites continues to hamper efforts to control this lethal disease. Dihydroorotate dehydrogenase has recently been validated as a new target for the treatment of malaria, and a selective inhibitor (DSM265) of the Plasmodium enzyme is currently in clinical development. With the goal of identifying a backup compound to DSM265, we explored replacement of the SF5-aniline moiety of DSM265 with a series of CF3-pyridinyls while maintaining the core triazolopyrimidine scaffold. This effort led to the identification of DSM421, which has improved solubility, lower intrinsic clearance, and increased plasma exposure after oral dosing compared to DSM265, while maintaining a long predicted human half-life. Its improved physical and chemical properties will allow it to be formulated more readily than DSM265. DSM421 showed excellent efficacy in the SCID mouse model of P. falciparum malaria that supports the prediction of a low human dose (<200 mg). Importantly DSM421 showed equal activity against both P. falciparum and P. vivax field isolates, while DSM265 was more active on P. falciparum. DSM421 has the potential to be developed as a single-dose cure or once-weekly chemopreventative for both P. falciparum and P. vivax malaria, leading to its advancement as a preclinical development candidate.
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Affiliation(s)
- Margaret A. Phillips
- Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Blvd, Dallas, Texas 75390-9041
| | - Karen L. White
- Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
| | - Sreekanth Kokkonda
- Departments of Chemistry and Global Health, University of Washington, Seattle, WA 98195
| | - Xiaoyi Deng
- Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Blvd, Dallas, Texas 75390-9041
| | - John White
- Departments of Chemistry and Global Health, University of Washington, Seattle, WA 98195
| | - Farah El Mazouni
- Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Blvd, Dallas, Texas 75390-9041
| | - Kennan Marsh
- Abbvie, 1 North Waukegan Road, North Chicago, Il 60064-6104
| | - Diana R. Tomchick
- Department of Biophysics, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Blvd, Dallas, Texas 75390-9041
| | | | | | - Grennady Wirjanata
- Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, PO Box 41096, Casuarina, NT 0811, Darwin, Australia
| | - Rintis Noviyanti
- Eijkman Institute for Molecular Biology, Jl. Diponegoro 69, 10430 Jakarta, Indonesia
| | - Ric N Price
- Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, PO Box 41096, Casuarina, NT 0811, Darwin, Australia
- Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, OX3 7LJ, UK
| | - Jutta Marfurt
- Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, PO Box 41096, Casuarina, NT 0811, Darwin, Australia
| | - David M. Shackleford
- Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
| | - Francis C.K. Chiu
- Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
| | - Michael Campbell
- Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
| | | | | | | | | | | | - Werner Kaminsky
- Departments of Chemistry and Global Health, University of Washington, Seattle, WA 98195
| | - Kigbafori Silue
- Centre Suisse de Recherches Scientifiques en Côte d’Ivoire (CSRS), Km17, Route de Dabou, Adiopodoumé, 01 BP 1303 Abidjan, Côte d’Ivoire
| | | | - Clemens Kocken
- Biomedical Primate Research Centre, Rijswijk, The Netherlands
| | - Didier Leroy
- Medicines for Malaria Venture, 1215 Geneva, Switzerland
| | | | | | | | - Dave Matthews
- Medicines for Malaria Venture, 1215 Geneva, Switzerland
| | | | | | | | - Pradipsinh K. Rathod
- Departments of Chemistry and Global Health, University of Washington, Seattle, WA 98195
| | - Susan A. Charman
- Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
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Diversity-oriented synthesis yields novel multistage antimalarial inhibitors. Nature 2016; 538:344-349. [PMID: 27602946 DOI: 10.1038/nature19804] [Citation(s) in RCA: 203] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 08/31/2016] [Indexed: 02/08/2023]
Abstract
Antimalarial drugs have thus far been chiefly derived from two sources-natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These molecules are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets.
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41
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Ren JX, Gao NN, Cao XS, Hu QA, Xie Y. Homology modeling and virtual screening for inhibitors of lipid kinase PI(4)K from Plasmodium. Biomed Pharmacother 2016; 83:798-808. [PMID: 27490781 DOI: 10.1016/j.biopha.2016.07.048] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 07/14/2016] [Accepted: 07/24/2016] [Indexed: 11/27/2022] Open
Abstract
Malaria parasite strains have emerged to tolerate the therapeutic effects of the prophylactics and drugs presently available. Recent studies have shown that KAI715 and its analogs inhibit malaria parasites growth by binding to lipid kinase PI(4)K (phosphatidylinositol-4-OH kinase) of the parasites. Therefore, targeting PI(4)K may open up new avenues of target-based drug discovery to identify novel anti-malaria drugs. In this investigation, we describe the discovery of novel potent PfPI(4)K (PI(4)K from P. falciparum) inhibitors by employing a proposed hybrid virtual screening (VS) method, including pharmacophore model, drug-likeness prediction and molecular docking approach. 3D structure of PfPI(4)K has been established by homology modeling. Pharmacophore model HypoA of PfPI(4)K inhibitors has been developed based on the ligand complexed with its corresponding receptor. 174 compounds with good ADMET properties were carefully selected by a hybrid virtual screening method. Finally, the 174 hits were further validated by using a new pharmacophore model HypoB built based on the docking pose of BQR685, and 95 compounds passed the last filter. These compounds would be further evaluated by biological activity assays. The molecular interactions of the top two potential inhibitors with the active site residues are discussed in detail. These identified hits can be further used for designing the more potent inhibitors against PfPI(4)K by scaffold hopping, and deserve consideration for further structure-activity relationship (SAR) studies.
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Affiliation(s)
- Ji-Xia Ren
- College of Life Science, Liaocheng University, Liaocheng 252059, People's Republic of China; Institute of Medicinal Plant Development, Chinese Academy of Medical Science & Peking Union Medical College, 151 Malianwa North Road, Haidian District, Beijing 100193, People's Republic of China
| | - Na-Na Gao
- Central Laboratory, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing 100038, People's Republic of China
| | - Xue-Song Cao
- College of Life Science, Liaocheng University, Liaocheng 252059, People's Republic of China
| | - Quan-An Hu
- College of Life Science, Liaocheng University, Liaocheng 252059, People's Republic of China
| | - Yong Xie
- Institute of Medicinal Plant Development, Chinese Academy of Medical Science & Peking Union Medical College, 151 Malianwa North Road, Haidian District, Beijing 100193, People's Republic of China.
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Raphemot R, Posfai D, Derbyshire ER. Current therapies and future possibilities for drug development against liver-stage malaria. J Clin Invest 2016; 126:2013-20. [PMID: 27249674 DOI: 10.1172/jci82981] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Malaria remains a global public health threat, with half of the world's population at risk. Despite numerous efforts in the past decade to develop new antimalarial drugs to surmount increasing resistance to common therapies, challenges remain in the expansion of the current antimalarial arsenal for the elimination of this disease. The requirement of prophylactic and radical cure activities for the next generation of antimalarial drugs demands that new research models be developed to support the investigation of the elusive liver stage of the malaria parasite. In this Review, we revisit current antimalarial therapies and discuss recent advances for in vitro and in vivo malaria research models of the liver stage and their importance in probing parasite biology and the discovery of novel drug candidates.
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Hovlid ML, Winzeler EA. Phenotypic Screens in Antimalarial Drug Discovery. Trends Parasitol 2016; 32:697-707. [PMID: 27247245 DOI: 10.1016/j.pt.2016.04.014] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 04/21/2016] [Indexed: 12/11/2022]
Abstract
Phenotypic high-throughput screens are a valuable tool for identifying new chemical compounds with antimalarial activity. Traditionally, these screens have focused solely on the symptomatic asexual blood stage of the parasite life cycle; however, to discover new medicines for malaria treatment and prevention, robust screening technologies against other parasite life-cycle stages are required. This review highlights recent advances and progress toward phenotypic screening methodologies over the past several years, with a focus on exoerythrocytic stage screens.
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Affiliation(s)
- Marisa L Hovlid
- School of Medicine, Department of Pediatrics, Division of Host-Microbe Systems and Therapeutics, University of California, San Diego (UCSD), 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Elizabeth A Winzeler
- School of Medicine, Department of Pediatrics, Division of Host-Microbe Systems and Therapeutics, University of California, San Diego (UCSD), 9500 Gilman Drive, La Jolla, CA 92093, USA.
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Phillips MA, Lotharius J, Marsh K, White J, Dayan A, White KL, Njoroge JW, El Mazouni F, Lao Y, Kokkonda S, Tomchick DR, Deng X, Laird T, Bhatia SN, March S, Ng CL, Fidock DA, Wittlin S, Lafuente-Monasterio M, Benito FJG, Alonso LMS, Martinez MS, Jimenez-Diaz MB, Bazaga SF, Angulo-Barturen I, Haselden JN, Louttit J, Cui Y, Sridhar A, Zeeman AM, Kocken C, Sauerwein R, Dechering K, Avery VM, Duffy S, Delves M, Sinden R, Ruecker A, Wickham KS, Rochford R, Gahagen J, Iyer L, Riccio E, Mirsalis J, Bathhurst I, Rueckle T, Ding X, Campo B, Leroy D, Rogers MJ, Rathod PK, Burrows JN, Charman SA. A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria. Sci Transl Med 2016; 7:296ra111. [PMID: 26180101 DOI: 10.1126/scitranslmed.aaa6645] [Citation(s) in RCA: 229] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Malaria is one of the most significant causes of childhood mortality, but disease control efforts are threatened by resistance of the Plasmodium parasite to current therapies. Continued progress in combating malaria requires development of new, easy to administer drug combinations with broad-ranging activity against all manifestations of the disease. DSM265, a triazolopyrimidine-based inhibitor of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH), is the first DHODH inhibitor to reach clinical development for treatment of malaria. We describe studies profiling the biological activity, pharmacological and pharmacokinetic properties, and safety of DSM265, which supported its advancement to human trials. DSM265 is highly selective toward DHODH of the malaria parasite Plasmodium, efficacious against both blood and liver stages of P. falciparum, and active against drug-resistant parasite isolates. Favorable pharmacokinetic properties of DSM265 are predicted to provide therapeutic concentrations for more than 8 days after a single oral dose in the range of 200 to 400 mg. DSM265 was well tolerated in repeat-dose and cardiovascular safety studies in mice and dogs, was not mutagenic, and was inactive against panels of human enzymes/receptors. The excellent safety profile, blood- and liver-stage activity, and predicted long half-life in humans position DSM265 as a new potential drug combination partner for either single-dose treatment or once-weekly chemoprevention. DSM265 has advantages over current treatment options that are dosed daily or are inactive against the parasite liver stage.
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Affiliation(s)
- Margaret A Phillips
- Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Boulevard, Dallas, TX 75390-9041, USA.
| | | | - Kennan Marsh
- Abbvie, 1 North Waukegan Road, North Chicago, IL 60064-6104, USA
| | - John White
- Departments of Chemistry and Global Health, University of Washington, Seattle, WA 98195, USA
| | - Anthony Dayan
- Medicines for Malaria Venture, 1215 Geneva, Switzerland
| | - Karen L White
- Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
| | - Jacqueline W Njoroge
- Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Boulevard, Dallas, TX 75390-9041, USA
| | - Farah El Mazouni
- Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Boulevard, Dallas, TX 75390-9041, USA
| | - Yanbin Lao
- Abbvie, 1 North Waukegan Road, North Chicago, IL 60064-6104, USA
| | - Sreekanth Kokkonda
- Departments of Chemistry and Global Health, University of Washington, Seattle, WA 98195, USA
| | - Diana R Tomchick
- Department of Biophysics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9041, USA
| | - Xiaoyi Deng
- Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Boulevard, Dallas, TX 75390-9041, USA
| | - Trevor Laird
- Medicines for Malaria Venture, 1215 Geneva, Switzerland
| | - Sangeeta N Bhatia
- Health Sciences and Technology/Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Sandra March
- Health Sciences and Technology/Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Caroline L Ng
- Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA
| | - David A Fidock
- Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA. Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
| | - Sergio Wittlin
- Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland. University of Basel, 4003 Basel, Switzerland
| | | | | | - Laura Maria Sanz Alonso
- GlaxoSmithKline (GSK), Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain
| | - Maria Santos Martinez
- GlaxoSmithKline (GSK), Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain
| | - Maria Belen Jimenez-Diaz
- GlaxoSmithKline (GSK), Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain
| | - Santiago Ferrer Bazaga
- GlaxoSmithKline (GSK), Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain
| | - Iñigo Angulo-Barturen
- GlaxoSmithKline (GSK), Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain
| | - John N Haselden
- GlaxoSmithKline (GSK), Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain
| | | | - Yi Cui
- GSK, Park Road, Ware, Hertfordshire SG12 0DP, UK
| | - Arun Sridhar
- GSK, Park Road, Ware, Hertfordshire SG12 0DP, UK
| | - Anna-Marie Zeeman
- Biomedical Primate Research Centre, P.O. Box 3306, 2280 GH Rijswijk, Netherlands
| | - Clemens Kocken
- Biomedical Primate Research Centre, P.O. Box 3306, 2280 GH Rijswijk, Netherlands
| | | | | | - Vicky M Avery
- Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia
| | - Sandra Duffy
- Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia
| | - Michael Delves
- Imperial College of Science Technology and Medicine, London SW7 2AY, UK
| | - Robert Sinden
- Imperial College of Science Technology and Medicine, London SW7 2AY, UK
| | - Andrea Ruecker
- Imperial College of Science Technology and Medicine, London SW7 2AY, UK
| | - Kristina S Wickham
- State University of New York Upstate Medical University, Syracuse, NY 13210, USA
| | - Rosemary Rochford
- State University of New York Upstate Medical University, Syracuse, NY 13210, USA
| | | | | | - Ed Riccio
- SRI International, Menlo Park, CA 94025, USA
| | | | - Ian Bathhurst
- Medicines for Malaria Venture, 1215 Geneva, Switzerland
| | | | - Xavier Ding
- Medicines for Malaria Venture, 1215 Geneva, Switzerland
| | - Brice Campo
- Medicines for Malaria Venture, 1215 Geneva, Switzerland
| | - Didier Leroy
- Medicines for Malaria Venture, 1215 Geneva, Switzerland
| | - M John Rogers
- National Institutes for Allergy and Infectious Diseases, 6610 Rockledge Drive, Bethesda, MD 20892, USA
| | - Pradipsinh K Rathod
- Departments of Chemistry and Global Health, University of Washington, Seattle, WA 98195, USA
| | | | - Susan A Charman
- Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
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PI4 Kinase Is a Prophylactic but Not Radical Curative Target in Plasmodium vivax-Type Malaria Parasites. Antimicrob Agents Chemother 2016; 60:2858-63. [PMID: 26926645 PMCID: PMC4862498 DOI: 10.1128/aac.03080-15] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Accepted: 02/19/2016] [Indexed: 01/04/2023] Open
Abstract
Two Plasmodium PI4 kinase (PI4K) inhibitors, KDU691 and LMV599, were selected for in vivo testing as causal prophylactic and radical-cure agents for Plasmodium cynomolgi sporozoite-infected rhesus macaques, based on their in vitro activity against liver stages. Animals were infected with P. cynomolgi sporozoites, and compounds were dosed orally. Both the KDU691 and LMV599 compounds were fully protective when administered prophylactically, and the more potent compound LMV599 achieved protection as a single oral dose of 25 mg/kg of body weight. In contrast, when tested for radical cure, five daily doses of 20 mg/kg of KDU691 or 25 mg/kg of LMV599 did not prevent relapse, as all animals experienced a secondary infection due to the reactivation of hypnozoites in the liver. Pharmacokinetic data show that LMV599 achieved plasma exposure that was sufficient to achieve efficacy based on our in vitro data. These findings indicate that Plasmodium PI4K is a potential drug target for malaria prophylaxis but not radical cure. Longer in vitro culture systems will be required to assess these compounds' activity on established hypnozoites and predict radical cure in vivo.
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Swann J, Corey V, Scherer CA, Kato N, Comer E, Maetani M, Antonova-Koch Y, Reimer C, Gagaring K, Ibanez M, Plouffe D, Zeeman AM, Kocken CHM, McNamara CW, Schreiber SL, Campo B, Winzeler EA, Meister S. High-Throughput Luciferase-Based Assay for the Discovery of Therapeutics That Prevent Malaria. ACS Infect Dis 2016; 2:281-293. [PMID: 27275010 PMCID: PMC4890880 DOI: 10.1021/acsinfecdis.5b00143] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2015] [Indexed: 11/29/2022]
Abstract
In order to identify the most attractive starting points for drugs that can be used to prevent malaria, a diverse chemical space comprising tens of thousands to millions of small molecules may need to be examined. Achieving this throughput necessitates the development of efficient ultra-high-throughput screening methods. Here, we report the development and evaluation of a luciferase-based phenotypic screen of malaria exoerythrocytic-stage parasites optimized for a 1536-well format. This assay uses the exoerythrocytic stage of the rodent malaria parasite, Plasmodium berghei, and a human hepatoma cell line. We use this assay to evaluate several biased and unbiased compound libraries, including two small sets of molecules (400 and 89 compounds, respectively) with known activity against malaria erythrocytic-stage parasites and a set of 9886 diversity-oriented synthesis (DOS)-derived compounds. Of the compounds screened, we obtain hit rates of 12-13 and 0.6% in preselected and naïve libraries, respectively, and identify 52 compounds with exoerythrocytic-stage activity less than 1 μM and having minimal host cell toxicity. Our data demonstrate the ability of this method to identify compounds known to have causal prophylactic activity in both human and animal models of malaria, as well as novel compounds, including some exclusively active against parasite exoerythrocytic stages.
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Affiliation(s)
- Justine Swann
- School of Medicine, Department of Pediatrics, Pharmacology & Drug Discovery, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Victoria Corey
- School of Medicine, Department of Pediatrics, Pharmacology & Drug Discovery, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Christina A. Scherer
- The Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, United States
| | - Nobutaka Kato
- The Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, United States
| | - Eamon Comer
- The Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, United States
| | - Micah Maetani
- The Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, United States
| | - Yevgeniya Antonova-Koch
- School of Medicine, Department of Pediatrics, Pharmacology & Drug Discovery, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Christin Reimer
- School of Medicine, Department of Pediatrics, Pharmacology & Drug Discovery, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Kerstin Gagaring
- Genomics Institute of the Novartis Research Foundation (GNF), 10675
John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Maureen Ibanez
- Genomics Institute of the Novartis Research Foundation (GNF), 10675
John Jay Hopkins Drive, San Diego, California 92121, United States
| | - David Plouffe
- Genomics Institute of the Novartis Research Foundation (GNF), 10675
John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Anne-Marie Zeeman
- Department of Parasitology, Biomedical Primate Research Centre, P.O. Box 3306, 2280 GH Rijswijk, The Netherlands
| | - Clemens H. M. Kocken
- Department of Parasitology, Biomedical Primate Research Centre, P.O. Box 3306, 2280 GH Rijswijk, The Netherlands
| | - Case W. McNamara
- The Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, United States
| | - Stuart L. Schreiber
- The Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, United States
| | - Brice Campo
- Medicines for Malaria Venture (MMV), Meyrin 2015, Switzerland
| | - Elizabeth A. Winzeler
- School of Medicine, Department of Pediatrics, Pharmacology & Drug Discovery, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Stephan Meister
- School of Medicine, Department of Pediatrics, Pharmacology & Drug Discovery, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
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47
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Noulin F. Malaria modeling: In vitro stem cells vs in vivo models. World J Stem Cells 2016; 8:88-100. [PMID: 27022439 PMCID: PMC4807312 DOI: 10.4252/wjsc.v8.i3.88] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 12/07/2015] [Accepted: 01/29/2016] [Indexed: 02/06/2023] Open
Abstract
The recent development of stem cell research and the possibility of generating cells that can be stably and permanently modified in their genome open a broad horizon in the world of in vitro modeling. The malaria field is gaining new opportunities from this important breakthrough and novel tools were adapted and opened new frontiers for malaria research. In addition to the new in vitro systems, in recent years there were also significant advances in the development of new animal models that allows studying the entire cell cycle of human malaria. In this paper, we review the different protocols available to study human Plasmodium species either by using stem cell or alternative animal models.
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48
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Mokgethi-Morule T, N'Da DD. Cell based assays for anti-Plasmodium activity evaluation. Eur J Pharm Sci 2016; 84:26-36. [PMID: 26776968 DOI: 10.1016/j.ejps.2016.01.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Revised: 12/28/2015] [Accepted: 01/02/2016] [Indexed: 10/22/2022]
Abstract
Malaria remains one of the most common and deadly infectious diseases worldwide. The severity of this global public health challenge is reflected by the approximately 198 million people, who were reportedly infected in 2013 and by the more than 584,000 related deaths in that same year. The rising emergence of drug resistance towards the once effective artemisinin combination therapies (ACTs) has become a serious concern and warrants more robust drug development strategies, with the objective of eradicating malaria infections. The intricate biology and life cycle of Plasmodium parasites complicate the understanding of the disease in such a way that would enhance the development of more effective chemotherapies that would achieve radical clinical cure and that would prevent disease relapse. Phenotypic cell based assays have for long been a valuable approach and involve the screening and analysis of diverse compounds with regards to their activities towards whole Plasmodium parasites in vitro. To achieve the Millennium Development Goal (MDG) of malaria eradication by 2020, new generation drugs that are active against all parasite stages (erythrocytic (blood), exo-erythrocytic (liver stages and gametocytes)) are needed. Significant advances are being made in assay development to overcome some of the practical challenges of assessing drug efficacy, particularly in the liver and transmission stage Plasmodium models. This review discusses primary screening models and the fundamental progress being made in whole cell based efficacy screens of anti-malarial activity. Ongoing challenges and some opportunities for improvements in assay development that would assist in the discovery of effective, safe and affordable drugs for malaria treatments are also discussed.
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Affiliation(s)
- Thabang Mokgethi-Morule
- Drug Design, Centre of Excellence for Pharmaceutical Sciences (PHARMACEN), North-West University, Potchefstroom 2520, South Africa
| | - David D N'Da
- Drug Design, Centre of Excellence for Pharmaceutical Sciences (PHARMACEN), North-West University, Potchefstroom 2520, South Africa.
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49
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Diagana TT. Supporting malaria elimination with 21st century antimalarial agent drug discovery. Drug Discov Today 2015; 20:1265-70. [PMID: 26103616 DOI: 10.1016/j.drudis.2015.06.009] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Revised: 05/27/2015] [Accepted: 06/15/2015] [Indexed: 12/26/2022]
Abstract
The burden of malaria has been considerably reduced over recent years. However, to achieve disease elimination, drug discovery for the next generation needs to focus on blocking disease transmission and on targeting the liver-stage forms of the parasite. Properties of the 'ideal' new antimalarial drug and the key scientific and technological advances that have led to recent progress in antimalarial drug discovery are reviewed. Using these advances, Novartis has built a robust pipeline of next-generation antimalarials. The preclinical and clinical development of two candidate drugs: KAE609 and KAF156, provide a framework for the path to breakthrough treatments that could be taking us a step closer to the vision of malaria elimination.
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Affiliation(s)
- Thierry T Diagana
- Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore.
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50
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Drug discovery for the developing world: progress at the Novartis Institute for Tropical Diseases. Nat Rev Drug Discov 2015; 14:442-4. [DOI: 10.1038/nrd4001-c1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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