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Giannakopoulou E, Akrani I, Mpekoulis G, Frakolaki E, Dimitriou M, Myrianthopoulos V, Vassilaki N, Zoidis G. Novel Pyrazino[1,2- a]indole-1,3(2 H,4 H)-dione Derivatives Targeting the Replication of Flaviviridae Viruses: Structural and Mechanistic Insights. Viruses 2024; 16:1238. [PMID: 39205212 PMCID: PMC11360281 DOI: 10.3390/v16081238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 06/27/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024] Open
Abstract
Infections with Flaviviridae viruses, such as hepatitis C (HCV), dengue (DENV), and yellow fever (YFV) viruses, are major public health problems worldwide. In the case of HCV, treatment is associated with drug resistance and high costs, while there is no clinically approved therapy for DENV and YFV. Consequently, there is still a need for new chemotherapies with alternative modes of action. We have previously identified novel 2-hydroxypyrazino[1,2-a]indole-1,3(2H,4H)-diones as metal-chelating inhibitors targeting HCV RNA replication. Here, by utilizing a structure-based approach, we rationally designed a second series of compounds by introducing various substituents at the indole core structure and at the imidic nitrogen, to improve specificity against the RNA-dependent RNA polymerase (RdRp). The resulting derivatives were evaluated for their potency against HCV genotype 1b, DENV2, and YFV-17D using stable replicon cell lines. The most favorable substitution was nitro at position 6 of the indole ring (compound 36), conferring EC50 1.6 μM against HCV 1b and 2.57 μΜ against HCV 1a, with a high selectivity index. Compound 52, carrying the acetohydroxamic acid functionality (-CH2CONHOH) on the imidic nitrogen, and compound 78, the methyl-substituted molecule at the position 4 indolediketopiperazine counterpart, were the most effective against DENV and YFV, respectively. Interestingly, compound 36 had a high genetic barrier to resistance and only one resistance mutation was detected, T181I in NS5B, suggesting that the compound target HCV RdRp is in accordance with our predicted model.
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Affiliation(s)
- Erofili Giannakopoulou
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, GR-15771 Athens, Greece; (E.G.); (I.A.); (V.M.)
| | - Ifigeneia Akrani
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, GR-15771 Athens, Greece; (E.G.); (I.A.); (V.M.)
| | - George Mpekoulis
- Molecular Virology Laboratory, Hellenic Pasteur Institute, Vas. Sofias Avenue, GR-11521 Athens, Greece; (G.M.); (M.D.)
| | - Efseveia Frakolaki
- Molecular Virology Laboratory, Hellenic Pasteur Institute, Vas. Sofias Avenue, GR-11521 Athens, Greece; (G.M.); (M.D.)
| | - Marios Dimitriou
- Molecular Virology Laboratory, Hellenic Pasteur Institute, Vas. Sofias Avenue, GR-11521 Athens, Greece; (G.M.); (M.D.)
| | - Vassilios Myrianthopoulos
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, GR-15771 Athens, Greece; (E.G.); (I.A.); (V.M.)
| | - Niki Vassilaki
- Molecular Virology Laboratory, Hellenic Pasteur Institute, Vas. Sofias Avenue, GR-11521 Athens, Greece; (G.M.); (M.D.)
| | - Grigoris Zoidis
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, GR-15771 Athens, Greece; (E.G.); (I.A.); (V.M.)
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Pardali V, Giannakopoulou E, Mpekoulis G, Tsopela V, Panos G, Taylor MC, Kelly JM, Vassilaki N, Zoidis G. Novel Lipophilic Hydroxamates Based on Spirocarbocyclic Hydantoin Scaffolds with Potent Antiviral and Trypanocidal Activity. Pharmaceuticals (Basel) 2023; 16:1046. [PMID: 37513957 PMCID: PMC10385743 DOI: 10.3390/ph16071046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/14/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Flaviviridae infections, such as those caused by hepatitis C (HCV) and dengue viruses (DENVs), represent global health risks. Infected people are in danger of developing chronic liver failure or hemorrhagic fever, both of which can be fatal if not treated. The tropical parasites Trypanosoma brucei and Trypanosoma cruzi cause enormous socioeconomic burdens in Sub-Saharan Africa and Latin America. Anti-HCV chemotherapy has severe adverse effects and is expensive, whereas dengue has no clinically authorized treatment. Antiparasitic medicines are often toxic and difficult to administer, and treatment failures are widely reported. There is an urgent need for new chemotherapies. Based on our previous research, we have undertaken structural modification of lead compound V with the goal of producing derivatives with both antiviral and trypanocidal activity. The novel spirocarbocyclic-substituted hydantoin analogs were designed, synthesized, and tested for antiviral activity against three HCV genotypes (1b, 3a, 4a), DENV, yellow fever virus (YFV), and two trypanosome species (T. brucei, T. cruzi). The optimization was successful and led to compounds with significant antiviral and trypanocidal activity and exceptional selectivity. Several modifications were made to further investigate the structure-activity relationships (SARs) and confirm the critical role of lipophilicity and conformational degrees of freedom.
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Affiliation(s)
- Vasiliki Pardali
- School of Health Sciences, Department of Pharmacy, Division of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece
| | - Erofili Giannakopoulou
- School of Health Sciences, Department of Pharmacy, Division of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece
| | - George Mpekoulis
- Molecular Virology Laboratory, Hellenic Pasteur Institute, Vas. Sofias Avenue, 11521 Athens, Greece
| | - Vassilina Tsopela
- Molecular Virology Laboratory, Hellenic Pasteur Institute, Vas. Sofias Avenue, 11521 Athens, Greece
| | - Georgios Panos
- Molecular Virology Laboratory, Hellenic Pasteur Institute, Vas. Sofias Avenue, 11521 Athens, Greece
| | - Martin C Taylor
- Department of Infection Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK
| | - John M Kelly
- Department of Infection Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK
| | - Niki Vassilaki
- Molecular Virology Laboratory, Hellenic Pasteur Institute, Vas. Sofias Avenue, 11521 Athens, Greece
| | - Grigoris Zoidis
- School of Health Sciences, Department of Pharmacy, Division of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece
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Leila AR, Mousa MHA, Frakolaki E, Vassilaki N, Bartenschlager R, Zoidis G, Abdel-Halim M, Abadi AH. Symmetric Anti-HCV Agents: Synthesis, Antiviral Properties, and Conformational Aspects of Core Scaffolds. ACS OMEGA 2019; 4:11440-11454. [PMID: 31460249 PMCID: PMC6682128 DOI: 10.1021/acsomega.9b01242] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 06/04/2019] [Indexed: 05/17/2023]
Abstract
As hepatitis C virus (HCV) is one of the major health problems in many countries, interest has been aroused in the design, synthesis, and optimization of novel NS5A inhibitors, outside the chemical space of currently available direct acting antivirals (DAAs). Two series of symmetric molecules with core scaffold 3,3'-(buta-1,3-diyne-1,4-diyl)dianiline or 4,4'-(buta-1,3-diyne-1,4-diyl)dianiline, coupled on its nitrogen as amide with different end caps, were synthesized and tested for their activities against HCV by using cell-based antiviral assays. Molecules with the 3,3'-(buta-1,3-diyne-1,4-diyl)dianiline core were more active than their 4,4'-congeners. Only the 3,3'-derivatives showed noncoplanarity of core phenyls that mostly led to a better interaction with the target protein and appears to be a crucial element for efficient inhibition of HCV replication. Compounds 2f and 2q exhibited potent inhibition of genotype (GT) 1b HCV replication with EC50 values in the picomolar range and selectivity index greater than 6 orders of magnitude. The compounds seem more selective toward GT 1b and 4a. In conclusion, novel symmetric molecules with a 3,3'-(buta-1,3-diyne-1,4-diyl)dianiline core are potent and selective inhibitors that provide new extension to explore the structure-activity relationship of NS5A targeting DAAs.
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Affiliation(s)
- Alaa R.
S. Leila
- Department
of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
| | - Mai H. A. Mousa
- Department
of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
| | - Efseveia Frakolaki
- Molecular
Virology Laboratory, Hellenic Pasteur Institute, Vas. Sofias Avenue, 11521 Athens, Greece
| | - Niki Vassilaki
- Molecular
Virology Laboratory, Hellenic Pasteur Institute, Vas. Sofias Avenue, 11521 Athens, Greece
| | - Ralf Bartenschlager
- Department
of Infectious Diseases, Molecular Virology, University of Heidelberg, 69117 Heidelberg, Germany
- German
Center for Infection Research, Heidelberg
Partner Site, 69120 Heidelberg, Germany
| | - Grigoris Zoidis
- School
of Health Sciences, Faculty of Pharmacy, Department of Pharmaceutical
Chemistry, University of Athens, Panepistimiopolis-Zografou, GR-15771 Athens, Greece
| | - Mohammad Abdel-Halim
- Department
of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
| | - Ashraf H. Abadi
- Department
of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
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Giannakopoulou E, Pardali V, Frakolaki E, Siozos V, Myrianthopoulos V, Mikros E, Taylor MC, Kelly JM, Vassilaki N, Zoidis G. Scaffold hybridization strategy towards potent hydroxamate-based inhibitors of Flaviviridae viruses and Trypanosoma species. MEDCHEMCOMM 2019; 10:991-1006. [PMID: 31303998 DOI: 10.1039/c9md00200f] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 05/15/2019] [Indexed: 12/14/2022]
Abstract
Infections with Flaviviridae viruses, such as hepatitis C virus (HCV) and dengue virus (DENV) pose global health threats. Infected individuals are at risk of developing chronic liver failure or haemorrhagic fever respectively, often with a fatal outcome if left untreated. Diseases caused by tropical parasites of the Trypanosoma species, T. brucei and T. cruzi, constitute significant socioeconomic burden in sub-Saharan Africa and continental Latin America, yet drug development is under-funded. Anti-HCV chemotherapy is associated with severe side effects and high cost, while dengue has no clinically approved therapy and antiparasitic drugs are outdated and difficult to administer. Moreover, drug resistance is an emerging concern. Consequently, the need for new revolutionary chemotherapies is urgent. By utilizing a molecular framework combination approach, we combined two distinct chemical entities with proven antiviral and trypanocidal activity into a novel hybrid scaffold attached by an acetohydroxamic acid group (CH2CONHOH), aiming at derivatives with dual activity. The novel spiro-carbocyclic substituted hydantoin analogues were rationally designed, synthesized and evaluated for their potency against three HCV genotypes (1b, 3a, 4a), DENV and two Trypanosoma species (T. brucei, T. cruzi). They exhibited significant EC50 values and remarkable selectivity indices. Several modifications were undertaken to further explore the structure activity relationships (SARs) and confirm the pivotal role of the acetohydroxamic acid metal binding group.
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Affiliation(s)
- Erofili Giannakopoulou
- School of Health Sciences , Faculty of Pharmacy , Department of Pharmaceutical Chemistry , National and Kapodistrian University of Athens , Panepistimiopolis-Zografou , GR-15771 Athens , Greece .
| | - Vasiliki Pardali
- School of Health Sciences , Faculty of Pharmacy , Department of Pharmaceutical Chemistry , National and Kapodistrian University of Athens , Panepistimiopolis-Zografou , GR-15771 Athens , Greece .
| | - Efseveia Frakolaki
- Molecular Virology Laboratory , Hellenic Pasteur Institute , Vas. Sofias Avenue , GR-11521 , Athens , Greece
| | - Vasileios Siozos
- Molecular Virology Laboratory , Hellenic Pasteur Institute , Vas. Sofias Avenue , GR-11521 , Athens , Greece
| | - Vassilios Myrianthopoulos
- School of Health Sciences , Faculty of Pharmacy , Department of Pharmaceutical Chemistry , National and Kapodistrian University of Athens , Panepistimiopolis-Zografou , GR-15771 Athens , Greece .
| | - Emmanuel Mikros
- School of Health Sciences , Faculty of Pharmacy , Department of Pharmaceutical Chemistry , National and Kapodistrian University of Athens , Panepistimiopolis-Zografou , GR-15771 Athens , Greece .
| | - Martin C Taylor
- Department of Pathogen Molecular Biology , London School of Hygiene and Tropical Medicine , Keppel Street , London WC1E 7HT , UK
| | - John M Kelly
- Department of Pathogen Molecular Biology , London School of Hygiene and Tropical Medicine , Keppel Street , London WC1E 7HT , UK
| | - Niki Vassilaki
- Molecular Virology Laboratory , Hellenic Pasteur Institute , Vas. Sofias Avenue , GR-11521 , Athens , Greece
| | - Grigoris Zoidis
- School of Health Sciences , Faculty of Pharmacy , Department of Pharmaceutical Chemistry , National and Kapodistrian University of Athens , Panepistimiopolis-Zografou , GR-15771 Athens , Greece .
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Esposito I, Marciano S, Trinks J. Pharmacokinetic and pharmacodynamic evaluation of daclatasvir, asunaprevir plus beclabuvir as a fixed-dose co-formulation for the treatment of hepatitis C. Expert Opin Drug Metab Toxicol 2018; 14:649-657. [PMID: 29855221 DOI: 10.1080/17425255.2018.1483336] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Many reports have evaluated the clinical efficacy and safety of the fixed-dose all-oral combination of daclatasvir, asunaprevir, and beclabuvir (DCV-TRIO), which was approved in Japan in December 2016 for the treatment of hepatitis C genotype (GT)-1 infection. Areas covered: This article reviews the pharmacodynamic and pharmacokinetic properties of the DCV-TRIO combination. The topics covered include data regarding the drug's absorption, distribution, metabolism, excretion, and antiviral activity strategies. Its therapeutic efficacy and safety in GT-1 infection from phase 2/3 clinical trials are also discussed. Expert opinion: The ideal regimen for the treatment of Hepatitis C virus infection should be potent, pangenotypic, Ribavirin-free, safe, co-formulated, and affordable. Considering these characteristics, DCV-TRIO is neither pangenotypic nor potent enough against GT-1a, regardless of the presence or absence of cirrhosis. Other potential limitations of this regimen are its dosification (twice-daily), and the fact that since it includes a protease inhibitor, it is contraindicated in decompensated cirrhosis. For these reasons, it has only been approved in Japan, where more than 70% of the patients are infected with GT-1b. However, this co-formulation might still have a place in the treatment of non-cirrhotic patients infected with GT-1b provided that massive access to treatment is facilitated.
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Affiliation(s)
- Isabella Esposito
- a Instituto de Ciencias Básicas y Medicina Experimental (ICBME), Instituto Universitario del Hospital Italiano , Buenos Aires , Argentina
| | - Sebastián Marciano
- b Hepatology Unit , Hospital Italiano de Buenos Aires , Buenos Aires , Argentina.,c Department of Research , Hospital Italiano de Buenos Aires , Buenos Aires , Argentina
| | - Julieta Trinks
- a Instituto de Ciencias Básicas y Medicina Experimental (ICBME), Instituto Universitario del Hospital Italiano , Buenos Aires , Argentina.,d National Council of Scientific and Technical Research (CONICET) , Buenos Aires , Argentina
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6
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Soriano V, Ramos JM, Barreiro P, Fernandez-Montero JV. AIDS Clinical Research in Spain-Large HIV Population, Geniality of Doctors, and Missing Opportunities. Viruses 2018; 10:v10060293. [PMID: 29848987 PMCID: PMC6024378 DOI: 10.3390/v10060293] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 05/24/2018] [Accepted: 05/25/2018] [Indexed: 02/07/2023] Open
Abstract
The first cases of AIDS in Spain were reported in 1982. Since then over 85,000 persons with AIDS have been cumulated, with 60,000 deaths. Current estimates for people living with HIV are of 145,000, of whom 20% are unaware of it. This explains the still high rate of late HIV presenters. Although the HIV epidemic in Spain was originally driven mostly by injection drug users, since the year 2000 men having sex with men (MSM) account for most new incident HIV cases. Currently, MSM represent over 80% of new yearly HIV diagnoses. In the 80s, a subset of young doctors and nurses working at Internal Medicine hospital wards became deeply engaged in attending HIV-infected persons. Before the introduction of antiretrovirals in the earlier 1990s, diagnosis and treatment of opportunistic infections was their major task. A new wave of infectious diseases specialists was born. Following the wide introduction of triple combination therapy in the late 1990s, drug side effects and antiretroviral resistance led to built a core of highly devoted HIV specialists across the country. Since then, HIV medicine has improved and currently is largely conducted by multidisciplinary teams of health care providers working at hospital-based outclinics, where HIV-positive persons are generally seen every six months. Antiretroviral therapy is currently prescribed to roughly 75,000 persons, almost all attended at clinics belonging to the government health public system. Overall, the impact of HIV/AIDS publications by Spanish teams is the third most important in Europe. HIV research in Spain has classically been funded mostly by national and European public agencies along with pharma companies. Chronologically, some of the major contributions of Spanish HIV research are being in the field of tuberculosis, toxoplasmosis, leishmaniasis, HIV variants including HIV-2, drug resistance, pharmacology, antiretroviral drug-related toxicities, coinfection with viral hepatitis, design and participation in clinical trials with antiretrovirals, immunopathogenesis, ageing, and vaccine development.
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Affiliation(s)
- Vicente Soriano
- Infectious Diseases Unit, La Paz University Hospital, 28046 Madrid, Spain.
- UNIR Health Sciences School, 28040 Madrid, Spain.
| | - José M Ramos
- Department of Internal Medicine, General University Hospital, 03010 Alicante, Spain.
| | - Pablo Barreiro
- Infectious Diseases Unit, La Paz University Hospital, 28046 Madrid, Spain.
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Ramsis TM, Abdel Karim SE, Vassilaki N, Frakolaki E, Kamal AAM, Zoidis G, Ahmed NS, Abadi AH. Expanding the chemical space of anti-HCV NS5A inhibitors by stereochemical exchange and peptidomimetic approaches. Arch Pharm (Weinheim) 2018; 351:e1800017. [PMID: 29799645 DOI: 10.1002/ardp.201800017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 04/28/2018] [Accepted: 05/02/2018] [Indexed: 02/05/2023]
Abstract
Here we report a series of potent anti-HCV agents bearing a symmetrical benzidine l-prolinamide backbone with different capping groups including alkyl/aryl carbamates of natural and unnatural valine and leucine amino acids. All compounds were investigated for their inhibitory activity in an HCV replicon assay on genotype 1b. The novel compounds share some chemical and clinical attributes of commercially available NS5A inhibitors. Compounds 5 and 6 with unnatural capping residue and ethyl and isobutyl carbamates showed EC50 values in the picomolar range with a low toxicity profile and selectivity indices of several orders of magnitude. These findings enlarge the chemical space from which NS5A inhibitors may be discovered by adopting unnatural amino acids, amino acids other than valine and carbamates other than methyl as the capping groups.
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Affiliation(s)
- Triveena M Ramsis
- Faculty of Pharmacy and Biotechnology, Department of Pharmaceutical Chemistry, German University in Cairo, Cairo, Egypt
| | - Shereen E Abdel Karim
- Faculty of Pharmacy and Biotechnology, Department of Pharmaceutical Chemistry, German University in Cairo, Cairo, Egypt
| | - Niki Vassilaki
- Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, Greece
| | - Efseveia Frakolaki
- Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, Greece
| | - Ahmed A M Kamal
- Pharmaceutical and Medicinal Chemistry, Department of Drug Design Optimization, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarbrücken, Germany
| | - Grigoris Zoidis
- Faculty of Pharmacy, Department of Pharmaceutical Chemistry, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece
| | - Nermin S Ahmed
- Faculty of Pharmacy and Biotechnology, Department of Pharmaceutical Chemistry, German University in Cairo, Cairo, Egypt
| | - Ashraf H Abadi
- Faculty of Pharmacy and Biotechnology, Department of Pharmaceutical Chemistry, German University in Cairo, Cairo, Egypt
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Flavonoids from Pterogyne nitens Inhibit Hepatitis C Virus Entry. Sci Rep 2017; 7:16127. [PMID: 29170411 PMCID: PMC5701011 DOI: 10.1038/s41598-017-16336-y] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Accepted: 11/09/2017] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) is one of the leading causes of liver diseases and transplantation worldwide. The current available therapy for HCV infection is based on interferon-α, ribavirin and the new direct-acting antivirals (DAAs), such as NS3 protease and NS5B polymerase inhibitors. However, the high costs of drug design, severe side effects and HCV resistance presented by the existing treatments demonstrate the need for developing more efficient anti-HCV agents. This study aimed to evaluate the antiviral effects of sorbifolin (1) and pedalitin (2), two flavonoids from Pterogyne nitens on the HCV replication cycle. These compounds were investigated for their anti-HCV activities using genotype 2a JFH-1 subgenomic replicons and infectious virus systems. Flavonoids 1 and 2 inhibited virus entry up to 45.0% and 78.7% respectively at non-cytotoxic concentrations. The mechanism of the flavonoid 2 block to virus entry was demonstrated to be by both the direct action on virus particles and the interference on the host cells. Alternatively, the flavonoid 1 activity was restricted to its virucidal effect. Additionally, no inhibitory effects on HCV replication and release were observed by treating cells with these flavonoids. These data are the first description of 1 and 2 possessing in vitro anti-HCV activity.
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9
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Soriano V, Benítez-Gutiérrez L, Arias A, Carrasco I, Barreiro P, Peña JM, de Mendoza C. Evaluation of sofosbuvir, velpatasvir plus voxilaprevir as fixed-dose co-formulation for treating hepatitis C. Expert Opin Drug Metab Toxicol 2017; 13:1015-1022. [PMID: 28753040 DOI: 10.1080/17425255.2017.1359254] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
INTRODUCTION The fixed-dose combination of three direct-acting antivirals (DAA), namely sofosbuvir, velpatasvir and voxilaprevir is the first pangenotypic, single tablet regimen developed for the treatment of HCV infection. Areas covered: The pharmacokinetics, pharmacodynamics, efficacy and safety of the co-formulation are reviewed. Information on drug absorption, distribution, metabolism and excretion of each of the three antivirals is evaluated. Finally, antiviral activity, safety and potential for drug interactions in phase II/III clinical trials in distinct patient populations are discussed. Expert opinion: The triple co-formulation of sofosbuvir-velpatasvir-voxilaprevir represents a major step towards HCV eradication. It depicts high efficacy even in patients infected with viruses harboring resistance-associated substitutions (RAS), including those selected after DAA failures. Likewise, very high success rates and good tolerance are seen in special patient populations, including decompensated cirrhotics, HIV coinfection, organ transplantation or renal insufficiency. A pill once daily for 8 weeks gives SVR rates above 95%. In prior DAA failures, extending treatment to 12 weeks maximizes SVR rates.
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Affiliation(s)
- Vicente Soriano
- a Infectious Diseases Unit , La Paz University Hospital & Autonomous University , Madrid , Spain
| | - Laura Benítez-Gutiérrez
- b Department of Internal Medicine , Puerta de Hierro Research Institute , Majadahonda , Spain
| | - Ana Arias
- b Department of Internal Medicine , Puerta de Hierro Research Institute , Majadahonda , Spain
| | - Itziar Carrasco
- b Department of Internal Medicine , Puerta de Hierro Research Institute , Majadahonda , Spain
| | - Pablo Barreiro
- a Infectious Diseases Unit , La Paz University Hospital & Autonomous University , Madrid , Spain
| | - Jose M Peña
- a Infectious Diseases Unit , La Paz University Hospital & Autonomous University , Madrid , Spain
| | - Carmen de Mendoza
- b Department of Internal Medicine , Puerta de Hierro Research Institute , Majadahonda , Spain
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10
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Lougiakis N, Frakolaki E, Karmou P, Pouli N, Marakos P, Madan V, Bartenschlager R, Vassilaki N. Novel nucleoside analogues targeting HCV replication through an NS5A-dependent inhibition mechanism. Chem Biol Drug Des 2017; 90:352-367. [PMID: 28245093 DOI: 10.1111/cbdd.12966] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Revised: 01/20/2017] [Accepted: 02/10/2017] [Indexed: 12/25/2022]
Abstract
A series of new tricyclic nucleosides were synthesized and evaluated as hepatitis C virus (HCV) replication inhibitors. Initial screening in a HCV replicon system, derived from a genotype 1b isolate, identified 9-benzylamino-3-(β-D-ribofuranosyl)-3H-imidazo[4',5':5,6]pyrido[2,3-b]pyrazine (15d) as the most potent analogue. Comparative assessment of 15d activity against HCV full-length viruses or subgenomic replicons derived from genotypes 1 to 4 revealed a specificity of the compound for genotypes 1 and 3. Surprisingly, resistance mutations selected against 15d were mapped to domains II and III of the non-structural protein 5A (NS5A), but not to the RNA-dependent RNA polymerase residing in NS5B. These results argue that compound 15d might represent a lead for the development of a novel class of NS5A inhibitors.
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Affiliation(s)
- Nikolaos Lougiakis
- Division of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
| | - Efseveia Frakolaki
- Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, Greece
| | - Panagiota Karmou
- Division of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
| | - Nicole Pouli
- Division of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Marakos
- Division of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
| | - Vanesa Madan
- Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Heidelberg, Germany
| | - Ralf Bartenschlager
- Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Heidelberg, Germany.,German Center for Infection Research, Heidelberg University, Heidelberg, Germany.,Division of Virus-Associated Carcinogenesis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Niki Vassilaki
- Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, Greece
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Velázquez-Moctezuma R, Law M, Bukh J, Prentoe J. Applying antibody-sensitive hypervariable region 1-deleted hepatitis C virus to the study of escape pathways of neutralizing human monoclonal antibody AR5A. PLoS Pathog 2017; 13:e1006214. [PMID: 28231271 PMCID: PMC5358973 DOI: 10.1371/journal.ppat.1006214] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Revised: 03/20/2017] [Accepted: 02/02/2017] [Indexed: 12/24/2022] Open
Abstract
Hepatitis C virus (HCV) is a major cause of end-stage liver diseases. With 3–4 million new HCV infections yearly, a vaccine is urgently needed. A better understanding of virus escape from neutralizing antibodies and their corresponding epitopes are important for this effort. However, for viral isolates with high antibody resistance, or antibodies with moderate potency, it remains challenging to induce escape mutations in vitro. Here, as proof-of-concept, we used antibody-sensitive HVR1-deleted (ΔHVR1) viruses to generate escape mutants for a human monoclonal antibody, AR5A, targeting a rare cross-genotype conserved epitope. By analyzing the genotype 1a envelope proteins (E1/E2) of recovered Core-NS2 recombinant H77/JFH1ΔHVR1 and performing reverse genetic studies we found that resistance to AR5A was caused by substitution L665W, also conferring resistance to the parental H77/JFH1. The mutation did not induce viral fitness loss, but abrogated AR5A binding to HCV particles and intracellular E1/E2 complexes. Culturing J6/JFH1ΔHVR1 (genotype 2a), for which fitness was decreased by L665W, with AR5A generated AR5A-resistant viruses with the substitutions I345V, L665S, and S680T, which we introduced into J6/JFH1 and J6/JFH1ΔHVR1. I345V increased fitness but had no effect on AR5A resistance. L665S impaired fitness and decreased AR5A sensitivity, while S680T combined with L665S compensated for fitness loss and decreased AR5A sensitivity even further. Interestingly, S680T alone had no fitness effect but sensitized the virus to AR5A. Of note, H77/JFH1L665S was non-viable. The resistance mutations did not affect cell-to-cell spread or E1/E2 interactions. Finally, introducing L665W, identified in genotype 1, into genotypes 2–6 parental and HVR1-deleted variants (not available for genotype 4a) we observed diverse effects on viral fitness and a universally pronounced reduction in AR5A sensitivity. Thus, we were able to take advantage of the neutralization-sensitive HVR1-deleted viruses to rapidly generate escape viruses aiding our understanding of the divergent escape pathways used by HCV to evade AR5A. Worldwide hepatitis C virus (HCV) is one of the leading causes of chronic liver diseases, including cirrhosis and cancer. Treatment accessibility is limited and development of a preventive vaccine has proven difficult, partly due to the high mutation rate of the virus. Recent studies of HCV antibody neutralization resistance have revealed important information about escape pathways and barriers to escape for several clinically promising human monoclonal antibodies. However, due to the varying levels of antibody shielding between HCV isolates these studies have been mostly limited to a few neutralization-sensitive HCV isolates. Here, we took advantage of the fact that deletion of the hypervariable region 1 (HVR1) increased antibody sensitivity of HCV isolates by increasing the exposure of important epitopes, thus facilitating studies of antibody escape for neutralization resistant isolates. We identified escape mutations in the envelope glycoprotein E2, at amino acid position L665, which conferred antibody resistance in parental HCV viruses from genotypes 1–6. We found that antibody escape was associated with loss of binding to HCV particles and intracellular envelope protein complexes. We also identified escape substitutions at L665 that were isolate-specific. Thus, our data sheds new light on antibody resistance mechanisms across diverse HCV isolates.
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Affiliation(s)
- Rodrigo Velázquez-Moctezuma
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases and Clinical Research Centre, Hvidovre Hospital and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Mansun Law
- Department of Immunology, The Scripps Research Institute, La Jolla, California, United States of America
| | - Jens Bukh
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases and Clinical Research Centre, Hvidovre Hospital and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
- * E-mail: (JP); (JB)
| | - Jannick Prentoe
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases and Clinical Research Centre, Hvidovre Hospital and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
- * E-mail: (JP); (JB)
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12
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Lam JT, Salazar L. New combination antiviral for the treatment of hepatitis C. Am J Health Syst Pharm 2016; 73:1042-50. [PMID: 27217519 DOI: 10.2146/ajhp150163] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
PURPOSE The pharmacology, pharmacokinetics, clinical efficacy, and safety of Viekira, as well as its place in hepatitis C virus (HCV) therapy, are reviewed. SUMMARY Ombitasvir 25 mg-paritaprevir 150 mg-ritonavir 100 mg plus dasabuvir 250 mg (Viekira) is approved in the United States as a combination direct-acting antiviral agent for treatment-naive or treatment-experienced patients with HCV genotype 1 infection, including those with compensated cirrhosis. It is the first coformulated direct-acting antiviral that targets different stages of the virus's life cycle. Viekira is administered as an oral, interferon-free regimen. Phase III clinical trials demonstrated that Viekira administered with or without ribavirin can achieve sustained virological response rates of ≥90%. These results are notable because they show that high virological cure rates can be achieved without peginterferon and ribavirin. Viekira is also effective for special patient populations, such as individuals coinfected with HIV, liver transplant recipients, and those with advanced renal disease. The most frequently reported adverse effects among patients associated with Viekira without ribavirin were nausea, pruritus, and insomnia. During clinical trials, the most common adverse effects among patients receiving Viekira with ribavirin were fatigue, nausea, pruritus, insomnia, and weakness. CONCLUSION Viekira, the first coformulated direct-acting antiviral that targets different stages of the HCV life cycle, is an interferon-free treatment for HCV genotype 1 infection. It is associated with a virological cure rate of ≥90% and treatment durations of 12 and 24 weeks. Viekira is also effective and safe for patients who have undergone liver transplantation, are coinfected with HIV, or have advanced kidney disease.
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Affiliation(s)
- Jerika T Lam
- Department of Pharmacy Practice, Chapman University School of Pharmacy, Irvine, CA.
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13
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Chuang H, Huang LCS, Kapoor M, Liao YJ, Yang CL, Chang CC, Wu CY, Hwu JR, Huang TJ, Hsu MH. Design and synthesis of pyridine-pyrazole-sulfonate derivatives as potential anti-HBV agents. MEDCHEMCOMM 2016. [DOI: 10.1039/c6md00008h] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hepatitis B virus (HBV) is an infectious disease, which can cause acute and chronic infections.
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Affiliation(s)
- Hong Chuang
- Department of Chemistry
- National Tsing Hua University
- Hsinchu 30013
- Taiwan
- Nuclear Science & Technology Development Centre
| | - Lin-Chiang Sherlock Huang
- Department of Chemistry
- National Tsing Hua University
- Hsinchu 30013
- Taiwan
- Nuclear Science & Technology Development Centre
| | - Mohit Kapoor
- Department of Chemistry
- National Tsing Hua University
- Hsinchu 30013
- Taiwan
| | - Yi-Jen Liao
- School of Medical Laboratory Science and Biotechnology
- College of Medical Science and Technology
- Taipei Medical University
- Taiwan
| | - Cheng-Lin Yang
- Graduate Institute of Biomedical Sciences
- National Chung Hsing University
- Taichung 402
- Taiwan
| | - Chia-Ching Chang
- Department of Biology Science and Technology
- National Chiao Tung University
- Hsinchu
- Taiwan
| | - Chun-Yi Wu
- Department of Biomedical Imaging and Radiological Science
- China Medical University
- Taichung
- Taiwan
| | - Jih Ru Hwu
- Department of Chemistry
- National Tsing Hua University
- Hsinchu 30013
- Taiwan
| | | | - Ming-Hua Hsu
- Nuclear Science & Technology Development Centre
- National Tsing Hua University
- Hsinchu 30013
- Taiwan
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Zoidis G, Giannakopoulou E, Stevaert A, Frakolaki E, Myrianthopoulos V, Fytas G, Mavromara P, Mikros E, Bartenschlager R, Vassilaki N, Naesens L. Novel indole–flutimide heterocycles with activity against influenza PA endonuclease and hepatitis C virus. MEDCHEMCOMM 2016. [DOI: 10.1039/c5md00439j] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Structure-based design and synthesis of novel indole–flutimide derivatives with antiviral activity.
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Affiliation(s)
- Grigoris Zoidis
- School of Health Sciences
- Faculty of Pharmacy
- Department of Pharmaceutical Chemistry
- National and Kapodistrian University of Athens
- Panepistimiopolis-Zografou
| | - Erofili Giannakopoulou
- School of Health Sciences
- Faculty of Pharmacy
- Department of Pharmaceutical Chemistry
- National and Kapodistrian University of Athens
- Panepistimiopolis-Zografou
| | - Annelies Stevaert
- Rega Institute for Medical Research
- KU Leuven – University of Leuven
- B-3000 Leuven
- Belgium
| | | | - Vassilios Myrianthopoulos
- School of Health Sciences
- Faculty of Pharmacy
- Department of Pharmaceutical Chemistry
- National and Kapodistrian University of Athens
- Panepistimiopolis-Zografou
| | - George Fytas
- School of Health Sciences
- Faculty of Pharmacy
- Department of Pharmaceutical Chemistry
- National and Kapodistrian University of Athens
- Panepistimiopolis-Zografou
| | | | - Emmanuel Mikros
- School of Health Sciences
- Faculty of Pharmacy
- Department of Pharmaceutical Chemistry
- National and Kapodistrian University of Athens
- Panepistimiopolis-Zografou
| | - Ralf Bartenschlager
- Department of Infectious Diseases
- Molecular Virology
- University of Heidelberg
- Heidelberg
- Germany
| | - Niki Vassilaki
- Molecular Virology Laboratory
- Hellenic Pasteur Institute
- Athens
- Greece
| | - Lieve Naesens
- Rega Institute for Medical Research
- KU Leuven – University of Leuven
- B-3000 Leuven
- Belgium
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15
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Lima VD, Rozada I, Grebely J, Hull M, Lourenco L, Nosyk B, Krajden M, Yoshida E, Wood E, Montaner JSG. Are Interferon-Free Direct-Acting Antivirals for the Treatment of HCV Enough to Control the Epidemic among People Who Inject Drugs? PLoS One 2015; 10:e0143836. [PMID: 26633652 PMCID: PMC4669174 DOI: 10.1371/journal.pone.0143836] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Accepted: 11/10/2015] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Widely access to interferon-free direct-acting antiviral regimens (IFN-free DAA) is poised to dramatically change the impact of the HCV epidemic among people who inject drugs (PWID). We evaluated the long-term effect of increasing HCV testing, treatment and engagement into harm-reduction activities, focused on active PWID, on the HCV epidemic in British Columbia (BC), Canada. METHODS We built a compartmental model of HCV disease transmission stratified by disease progression, transmission risk, and fibrosis level. We explored the effect of: (1) Increasing treatment rates from 8 to 20, 40 and 80 per 1000 infected PWID/year; (2) Increasing treatment eligibility based on fibrosis level; (3) Maximizing the effect of testing by performing it immediately upon ending the acute phase; (4) Increasing access to harm-reduction activities to reduce the risk of re-infection; (5) Different HCV antiviral regimens on the Control Reproduction Number Rc. We assessed the impact of these interventions on incidence, prevalence and mortality from 2016 to 2030. RESULTS Of all HCV antiviral regimens, only IFN-free DAAs offered a high chance of disease elimination (i.e. Rc < 1), but it would be necessary to substantially increase the current low testing and treatment rates. Assuming a treatment rate of 80 per 1000 infected PWID per year, coupled with a high testing rate, the incidence rate, at the end of 2030, could decrease from 92.9 per 1000 susceptible PWID per year (Status Quo) to 82.8 (by treating only PWID with fibrosis level F2 and higher) or to 65.5 (by treating PWID regardless of fibrosis level). If PWID also had access to increased harm-reduction activities, the incidence rate further decreased to 53.1 per 1000 susceptible PWID per year. We also obtained significant decreases in prevalence and mortality at the end of 2030. CONCLUSIONS The combination of increased access to HCV testing, highly efficacious antiviral treatment and harm-reduction programs can substantially decrease the burden of the HCV epidemic among PWID. However, unless we increase the current levels of treatment and testing, the HCV epidemic among PWID in BC, and in other parts of the world with similar epidemiological background, will remain a substantial public health concern for many years.
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Affiliation(s)
- Viviane D. Lima
- British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada
| | - Ignacio Rozada
- British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada
| | - Jason Grebely
- The Kirby Institute, University of New South Wales Australia, Sydney, NSW, Australia
| | - Mark Hull
- British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada
| | - Lillian Lourenco
- British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada
| | - Bohdan Nosyk
- British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada
| | - Mel Krajden
- Public Health Microbiology and Reference Laboratory, British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada
| | - Eric Yoshida
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Evan Wood
- British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada
| | - Julio S. G. Montaner
- British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada
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16
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Rashidzadeh H, Bhadresa S, Good SS, Larsson Cohen M, Gupta KS, Rush WR. Overcoming stability challenges in the quantification of tissue nucleotides: determination of 2'-C-methylguanosine triphosphate concentration in mouse liver. Biol Pharm Bull 2015; 38:380-8. [PMID: 25757919 DOI: 10.1248/bpb.b14-00565] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
A conventional, rapid and high throughput method for tissue extraction and accurate and selective LC-MS/MS quantification of 2'-C-methylguanosine triphosphate (2'-MeGTP) in mouse liver was developed and qualified. Trichloroacetic acid (TCA) was used as the tissue homogenization reagent that overcomes instability challenges of liver tissue nucleotide triphosphates due to instant ischemic degradation to mono- and diphosphate nucleotides. Degradation of 2'-MeGTP was also minimized by harvesting livers using in situ clamp-freezing or snap-freezing techniques. The assay also included a sample clean-up procedure using weak anion exchange solid phase extraction followed by ion exchange chromatography and tandem mass spectrometry detection. The linear assay range was from 50 to 10000 pmol/mL concentration in liver homogenate (250-50000 pmol/g in liver tissue). The method was qualified over three intraday batches for accuracy, precision, selectivity and specificity. The assay was successfully applied to pharmacokinetic studies of 2'-MeGTP in liver tissue samples after single oral doses of IDX184, a nucleotide prodrug inhibitor of the viral polymerase for the treatment of hepatitis C, to mice. The study results suggested that the clamp-freezing liver collection method was marginally more effective in preventing 2'-MeGTP degradation during liver tissue collection compared to the snap-freezing method.
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17
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Gentile I, Zappulo E, Buonomo AR, Scotto R, Borgia G. Asunaprevir for hepatitis C: a safety evaluation. Expert Opin Drug Saf 2015; 14:1631-46. [PMID: 26329454 DOI: 10.1517/14740338.2015.1084287] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION The introduction of direct-acting antiviral (DAA) agents has revolutionized the treatment of hepatitis C virus (HCV) chronic infection. Non-structural 3 protease inhibitors are currently the most numerous class of DAAs on the market. AREAS COVERED This review mainly focuses on the tolerability and safety profile of asunaprevir (ASV)-containing DAA regimens. ASV is a second-wave protease inhibitor currently in Phase III clinical development in most countries and already available in Japan. EXPERT OPINION ASV shows potent antiviral effect and clinical efficacy on HCV genotypes 1 and 4. The all-oral combination daclatasvir/ASV reached high eradication rates in HCV genotype 1b and 4 infection, and a lower efficacy in genotype 1a infection. ASV presents a low potential for drug-drug interaction and a good tolerability as part of multiple, including all-oral, regimens. ASV is associated with a transient and usually mild increase in aminotransferase levels in a low percentage of cases. Due to the impaired pharmacokinetic profile observed in advanced liver disease, ASV use in patients with moderate or severe hepatic impairment is not allowed. In conclusion, ASV represents a powerful weapon against HCV infection and has to be considered an optimal option as a component of genotype tailored interferon-free combinations.
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Affiliation(s)
- Ivan Gentile
- a University of Naples "Federico II", Department of Clinical Medicine and Surgery , via S. Pansini 5, I-80131 Naples, Italy +39 081 746 3178 ; +39 081 746 3190 ;
| | - Emanuela Zappulo
- a University of Naples "Federico II", Department of Clinical Medicine and Surgery , via S. Pansini 5, I-80131 Naples, Italy +39 081 746 3178 ; +39 081 746 3190 ;
| | - Antonio Riccardo Buonomo
- a University of Naples "Federico II", Department of Clinical Medicine and Surgery , via S. Pansini 5, I-80131 Naples, Italy +39 081 746 3178 ; +39 081 746 3190 ;
| | - Riccardo Scotto
- a University of Naples "Federico II", Department of Clinical Medicine and Surgery , via S. Pansini 5, I-80131 Naples, Italy +39 081 746 3178 ; +39 081 746 3190 ;
| | - Guglielmo Borgia
- a University of Naples "Federico II", Department of Clinical Medicine and Surgery , via S. Pansini 5, I-80131 Naples, Italy +39 081 746 3178 ; +39 081 746 3190 ;
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18
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Miot C, Beaumont E, Duluc D, Le Guillou-Guillemette H, Preisser L, Garo E, Blanchard S, Hubert Fouchard I, Créminon C, Lamourette P, Fremaux I, Calès P, Lunel-Fabiani F, Boursier J, Braum O, Fickenscher H, Roingeard P, Delneste Y, Jeannin P. IL-26 is overexpressed in chronically HCV-infected patients and enhances TRAIL-mediated cytotoxicity and interferon production by human NK cells. Gut 2015; 64:1466-75. [PMID: 25183206 DOI: 10.1136/gutjnl-2013-306604] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Accepted: 08/16/2014] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Interleukin-26 (IL-26) is a member of the IL-10 cytokine family, first discovered based on its peculiar expression by virus-transformed T cells. IL-26 is overexpressed in chronic inflammation (rheumatoid arthritis and Crohn's disease) and induces proinflammatory cytokines by myeloid cells and some epithelial cells. We thus investigated the expression and potential role of IL-26 in chronic HCV infection, a pathology associated with chronic inflammation. DESIGN IL-26 was quantified in a cohort of chronically HCV-infected patients, naive of treatment and its expression in the liver biopsies investigated by immunohistochemistry. We also analysed the ability of IL-26 to modulate the activity of natural killer (NK) cells, which control HCV infection. RESULTS The serum levels of IL-26 are enhanced in chronically HCV-infected patients, mainly in those with severe liver inflammation. Immunohistochemistry reveals an intense IL-26 staining in liver lesions, mainly in infiltrating CD3+ cells. We also show that NK cells from healthy subjects and from HCV-infected patients are sensitive to IL-26. IL-26 upregulates membrane tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) expression on CD16- CD56(bright) NK cells, enabling them to kill HCV-infected hepatoma cells, with the same efficacy as interferon (IFN)-α-treated NK cells. IL-26 also induces the expression of the antiviral cytokines IFN-β and IFN-γ, and of the proinflammatory cytokines IL-1β and TNF-α by NK cells. CONCLUSIONS This study highlights IL-26 as a new player in the inflammatory and antiviral immune responses associated with chronic HCV infection.
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Affiliation(s)
- Charline Miot
- Université d'Angers, Angers, France Inserm, Unité 892, Angers, France CNRS, Unité 6299, Angers, France Laboratoire d'Immunologie et Allergologie, CHU Angers, Angers, France
| | - Elodie Beaumont
- Université de Tours, Tours, France Inserm, Unité 966, Tours, France
| | - Dorothée Duluc
- Université d'Angers, Angers, France Inserm, Unité 892, Angers, France CNRS, Unité 6299, Angers, France
| | | | - Laurence Preisser
- Université d'Angers, Angers, France Inserm, Unité 892, Angers, France CNRS, Unité 6299, Angers, France
| | - Erwan Garo
- Université d'Angers, Angers, France Inserm, Unité 892, Angers, France CNRS, Unité 6299, Angers, France
| | - Simon Blanchard
- Université d'Angers, Angers, France Inserm, Unité 892, Angers, France CNRS, Unité 6299, Angers, France Laboratoire d'Immunologie et Allergologie, CHU Angers, Angers, France
| | | | - Christophe Créminon
- Service de Pharmacologie et d'Immunoanalyse, Commissariat à l'Energie Atomique Saclay, iBiTec-S, Gif sur Yvette, France
| | - Patricia Lamourette
- Service de Pharmacologie et d'Immunoanalyse, Commissariat à l'Energie Atomique Saclay, iBiTec-S, Gif sur Yvette, France
| | - Isabelle Fremaux
- Université d'Angers, Angers, France Inserm, Unité 892, Angers, France CNRS, Unité 6299, Angers, France
| | - Paul Calès
- Université d'Angers, UPRES 3859, Angers, France Service d'Hépato-Gastroentérologie, CHU Angers, Angers, France
| | - Françoise Lunel-Fabiani
- Laboratoire de Bactériologie-Virologie, CHU Angers, Angers, France Université d'Angers, UPRES 3859, Angers, France
| | - Jérôme Boursier
- Service d'Hépato-Gastroentérologie, CHU Angers, Angers, France
| | - Oliver Braum
- Institute for Infection Medicine, Christian Albrecht University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Helmut Fickenscher
- Institute for Infection Medicine, Christian Albrecht University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
| | | | - Yves Delneste
- Université d'Angers, Angers, France Inserm, Unité 892, Angers, France CNRS, Unité 6299, Angers, France Laboratoire d'Immunologie et Allergologie, CHU Angers, Angers, France
| | - Pascale Jeannin
- Université d'Angers, Angers, France Inserm, Unité 892, Angers, France CNRS, Unité 6299, Angers, France Laboratoire d'Immunologie et Allergologie, CHU Angers, Angers, France
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Yang DR, Zhu HZ. Hepatitis C virus and antiviral innate immunity: Who wins at tug-of-war? World J Gastroenterol 2015; 21:3786-3800. [PMID: 25852264 PMCID: PMC4385526 DOI: 10.3748/wjg.v21.i13.3786] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Revised: 01/21/2015] [Accepted: 02/13/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is a major human pathogen of chronic hepatitis and related liver diseases. Innate immunity is the first line of defense against invading foreign pathogens, and its activation is dependent on the recognition of these pathogens by several key sensors. The interferon (IFN) system plays an essential role in the restriction of HCV infection via the induction of hundreds of IFN-stimulated genes (ISGs) that inhibit viral replication and spread. However, numerous factors that trigger immune dysregulation, including viral factors and host genetic factors, can help HCV to escape host immune response, facilitating viral persistence. In this review, we aim to summarize recent advances in understanding the innate immune response to HCV infection and the mechanisms of ISGs to suppress viral survival, as well as the immune evasion strategies for chronic HCV infection.
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20
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Horner SM. Insights into antiviral innate immunity revealed by studying hepatitis C virus. Cytokine 2015; 74:190-7. [PMID: 25819428 DOI: 10.1016/j.cyto.2015.03.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Accepted: 03/04/2015] [Indexed: 02/07/2023]
Abstract
Experimental studies on the interactions of the positive strand RNA virus hepatitis C virus (HCV) with the host have contributed to several discoveries in the field of antiviral innate immunity. These include revealing the antiviral sensing pathways that lead to the induction of type I interferon (IFN) during HCV infection and also the importance of type III IFNs in the antiviral immune response to HCV. These studies on HCV/host interactions have contributed to our overall understanding of viral sensing and viral evasion of the antiviral intracellular innate immune response. In this review, I will highlight how these studies of HCV/host interactions have led to new insights into antiviral innate immunity. Overall, I hope to emphasize that studying antiviral immunity in the context of virus infection is necessary to fully understand antiviral immunity and how it controls the outcome of viral infection.
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Affiliation(s)
- Stacy M Horner
- Department of Molecular Genetics & Microbiology, Duke University Medical Center, Durham, NC 27710, United States; Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States.
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21
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A new role for PGA1 in inhibiting hepatitis C virus-IRES-mediated translation by targeting viral translation factors. Antiviral Res 2015; 117:1-9. [PMID: 25666760 DOI: 10.1016/j.antiviral.2015.01.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Revised: 01/26/2015] [Accepted: 01/29/2015] [Indexed: 02/06/2023]
Abstract
Previous studies have demonstrated that cyclopentenone prostaglandins (cyPGs) inhibit the replication of a wide variety of DNA and RNA viruses in different mammalian cell types. We investigated a new role for prostaglandin A1 (PGA1) in the inhibition of hepatitis C virus (HCV)-IRES-mediated translation. PGA1 exhibited dose-dependent inhibitory effects on HCV translation in HCV replicon cells. Furthermore, repetitive PGA1 treatment demonstrated the potential to safely induce the suppression of HCV translation. We also validated a new role for PGA1 in the inhibition of HCV-IRES-mediated translation by targeting cellular translation factors, including the small ribosomal subunit (40S) and eukaryotic initiation factors (eIFs). In pull-down assays, biotinylated PGA1 co-precipitated with the entire HCV IRES RNA/eIF3-40S subunit complex. Moreover, the interactions between PGA1 and the elongation factors and ribosomal subunit were dependent upon HCV IRES RNA binding, and the PGA1/HCV IRES RNA/eIF3-40S subunit complex inhibited HCV-IRES-mediated translation. The novel mechanism revealed in this study may aid in the search for more effective anti-HCV drugs.
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Kosaka K, Imamura M, Hayes CN, Abe H, Hiraga N, Yoshimi S, Murakami E, Kawaoka T, Tsuge M, Aikata H, Miki D, Ochi H, Matsui H, Kanai A, Inaba T, Chayama K. Emergence of resistant variants detected by ultra-deep sequencing after asunaprevir and daclatasvir combination therapy in patients infected with hepatitis C virus genotype 1. J Viral Hepat 2015; 22:158-65. [PMID: 24943406 DOI: 10.1111/jvh.12271] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Daclatasvir (DCV) and asunaprevir (ASV) are NS5A and NS3 protease-targeted antivirals respectively, currently under development for the treatment of chronic hepatitis C virus (HCV) infection. We analysed the relationship between pre-existing drug-resistant variants and clinical outcome of the combination treatment with DCV and ASV. Ten patients with HCV genotype 1b were orally treated with a combination of ASV and DCV for 24 weeks. The frequencies of amino acid (aa) variants at NS3 aa positions 155, 156 and 168 and at NS5A aa31 and 93 before and after treatment were analysed by ultra-deep sequencing. We established a minimum variant frequency threshold of 0.3% based on plasmid sequencing. Sustained virological response (SVR) was achieved in 8 out of 10 patients (80%), and relapse of HCV RNA after cessation of the treatment and viral breakthrough occurred in the other two patients. Pre-existing DCV-resistant variants (L31V/M and/or Y93H; 0.9-99.4%) were detected in three out of eight patients who achieved SVR. Pre-existing DCV-resistant variants were detected in a relapsed patient (L31M, Y93H) and in a patient with viral breakthrough (Y93H); however, no ASV-resistant variants were detected. In these patients, HCV RNA rebounded with ASV- and DCV- double resistant variants (NS3 D168A/V plus NS5A L31M and Y93H). While pre-existing DCV-resistant variants might contribute to viral breakthrough in DCV and ASV combination therapy, the effectiveness of prediction of the outcome of therapy based on ultra-deep sequence analysis of pre-existing resistant variants appears limited.
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Affiliation(s)
- K Kosaka
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
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Guan Y, Sun H, Pan P, Li Y, Li D, Hou T. Exploring resistance mechanisms of HCV NS3/4A protease mutations to MK5172: insight from molecular dynamics simulations and free energy calculations. MOLECULAR BIOSYSTEMS 2015. [DOI: 10.1039/c5mb00394f] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Mutations at a number of key positions (Ala156, Asp168 and Arg155) of the HCV NS3/4A protease can induce medium to high resistance to MK5172.
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Affiliation(s)
- Yan Guan
- College of Pharmaceutical Sciences
- Zhejiang University
- Hangzhou
- China
- Institute of Functional Nano & Soft Materials (FUNSOM)
| | - Huiyong Sun
- College of Pharmaceutical Sciences
- Zhejiang University
- Hangzhou
- China
| | - Peichen Pan
- College of Pharmaceutical Sciences
- Zhejiang University
- Hangzhou
- China
| | - Youyong Li
- Institute of Functional Nano & Soft Materials (FUNSOM)
- Soochow University
- Suzhou
- China
| | - Dan Li
- College of Pharmaceutical Sciences
- Zhejiang University
- Hangzhou
- China
| | - Tingjun Hou
- College of Pharmaceutical Sciences
- Zhejiang University
- Hangzhou
- China
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24
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Alibek K, Irving S, Sautbayeva Z, Kakpenova A, Bekmurzayeva A, Baiken Y, Imangali N, Shaimerdenova M, Mektepbayeva D, Balabiyev A, Chinybayeva A. Disruption of Bcl-2 and Bcl-xL by viral proteins as a possible cause of cancer. Infect Agent Cancer 2014; 9:44. [PMID: 25699089 PMCID: PMC4333878 DOI: 10.1186/1750-9378-9-44] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 11/25/2014] [Indexed: 01/01/2023] Open
Abstract
The Bcl proteins play a critical role in apoptosis, as mutations in family members interfere with normal programmed cell death. Such events can cause cell transformation, potentially leading to cancer. Recent discoveries indicate that some viral proteins interfere with Bcl proteins either directly or indirectly; however, these data have not been systematically described. Some viruses encode proteins that reprogramme host cellular signalling pathways controlling cell differentiation, proliferation, genomic integrity, cell death, and immune system recognition. This review analyses and summarises the existing data and discusses how viral proteins interfere with normal pro- and anti-apoptotic functions of Bcl-2 and Bcl-xL. Particularly, this article focuses on how viral proteins, such as Herpesviruses, HTLV-1, HPV and HCV, block apoptosis and how accumulation of such interference predisposes cancer development. Finally, we discuss possible ways to prevent and treat cancers using a combination of traditional therapies and antiviral preparations that are effective against these viruses.
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Affiliation(s)
- Kenneth Alibek
- Nazarbayev University Research and Innovation System (NURIS), Nazarbayev University, 53 Kabanbay Batyr Avenue, Astana, 010000 Kazakhstan ; National Medical Holding, 2 Syganak Street, Astana, 010000 Kazakhstan
| | - Stephanie Irving
- Nazarbayev University Research and Innovation System (NURIS), Nazarbayev University, 53 Kabanbay Batyr Avenue, Astana, 010000 Kazakhstan
| | - Zarina Sautbayeva
- Nazarbayev University Research and Innovation System (NURIS), Nazarbayev University, 53 Kabanbay Batyr Avenue, Astana, 010000 Kazakhstan
| | - Ainur Kakpenova
- Nazarbayev University Research and Innovation System (NURIS), Nazarbayev University, 53 Kabanbay Batyr Avenue, Astana, 010000 Kazakhstan
| | - Aliya Bekmurzayeva
- Nazarbayev University Research and Innovation System (NURIS), Nazarbayev University, 53 Kabanbay Batyr Avenue, Astana, 010000 Kazakhstan
| | - Yeldar Baiken
- Nazarbayev University Research and Innovation System (NURIS), Nazarbayev University, 53 Kabanbay Batyr Avenue, Astana, 010000 Kazakhstan
| | - Nurgul Imangali
- School of Science and Technology, Nazarbayev University, 53 Kabanbay Batyr Avenue, Astana, 010000 Kazakhstan
| | - Madina Shaimerdenova
- School of Science and Technology, Nazarbayev University, 53 Kabanbay Batyr Avenue, Astana, 010000 Kazakhstan
| | - Damel Mektepbayeva
- Nazarbayev University Research and Innovation System (NURIS), Nazarbayev University, 53 Kabanbay Batyr Avenue, Astana, 010000 Kazakhstan
| | - Arnat Balabiyev
- Nazarbayev University Research and Innovation System (NURIS), Nazarbayev University, 53 Kabanbay Batyr Avenue, Astana, 010000 Kazakhstan
| | - Aizada Chinybayeva
- Nazarbayev University Research and Innovation System (NURIS), Nazarbayev University, 53 Kabanbay Batyr Avenue, Astana, 010000 Kazakhstan
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25
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Kayali Z, Schmidt WN. Finally sofosbuvir: an oral anti-HCV drug with wide performance capability. Pharmgenomics Pers Med 2014; 7:387-98. [PMID: 25540594 PMCID: PMC4270038 DOI: 10.2147/pgpm.s52629] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Chronic Hepatitis C virus (HCV) infection is the leading cause of advanced liver disease worldwide. The virus successfully evades host immune detection and for many years has hampered efforts to find a safe, uncomplicated, and reliable oral antiviral therapy. Initially, interferon and ribavirin therapy was the treatment standard of care, but it offered limited performance across the wide spectrum of HCV disease and was fraught with excessive and often limiting side effects. Sofosbuvir (SOF) is a potent first-in-class nucleoside inhibitor that has recently been approved for treatment of HCV. The drug has low toxicity, a high resistance barrier, and minimal drug interactions with other HCV direct-acting antiviral agents such as protease inhibitors or anti-NS5A agents. SOF is safe and can be used across different viral genotypes, disease stages, and special patient groups, such as those coinfected with human immunodeficiency virus. When used in combination with ribavirin or another direct-acting antiviral agent, SOF has revolutionized the HCV treatment spectrum and set the stage for nearly universal HCV antiviral therapy. More so than any other anti-HCV drug developed to date, SOF offers the widest applicability for all infected patients, and new regimens will be tailored to maximize performance.
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Affiliation(s)
- Zeid Kayali
- Division of Gastroenterology and Hepatology, University of Southern California, Los Angeles, CA, USA
| | - Warren N Schmidt
- Department of Internal Medicine and Research Service, Veterans Affairs Medical Center, Iowa City, IA, USA
- Roy G and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, USA
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26
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Keri RS, Hiremathad A, Budagumpi S, Nagaraja BM. Comprehensive Review in Current Developments of Benzimidazole-Based Medicinal Chemistry. Chem Biol Drug Des 2014; 86:19-65. [PMID: 25352112 DOI: 10.1111/cbdd.12462] [Citation(s) in RCA: 214] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Accepted: 10/12/2014] [Indexed: 12/13/2022]
Abstract
The properties of benzimidazole and its derivatives have been studied over more than one hundred years. Benzimidazole derivatives are useful intermediates/subunits for the development of molecules of pharmaceutical or biological interest. Substituted benzimidazole derivatives have found applications in diverse therapeutic areas such as antiulcer, anticancer agents, and anthelmintic species to name just a few. This work systematically gives a comprehensive review in current developments of benzimidazole-based compounds in the whole range of medicinal chemistry as anticancer, antibacterial, antifungal, anti-inflammatory, analgesic agents, anti-HIV, antioxidant, anticonvulsant, antitubercular, antidiabetic, antileishmanial, antihistaminic, antimalarial agents, and other medicinal agents. This review will further be helpful for the researcher on the basis of substitution pattern around the nucleus with an aim to help medicinal chemists for developing an SAR on benzimidazole drugs/compounds.
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Affiliation(s)
- Rangappa S Keri
- Centre for Nano and Material Sciences, Jain University, Jain Global Campus, Bangalore, Karnataka, 562112, India
| | - Asha Hiremathad
- Centre for Nano and Material Sciences, Jain University, Jain Global Campus, Bangalore, Karnataka, 562112, India
| | - Srinivasa Budagumpi
- Centre for Nano and Material Sciences, Jain University, Jain Global Campus, Bangalore, Karnataka, 562112, India
| | - Bhari Mallanna Nagaraja
- Centre for Nano and Material Sciences, Jain University, Jain Global Campus, Bangalore, Karnataka, 562112, India
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27
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Replication priority of hepatitis C virus genotype 2a in a Chinese cohort. Acta Pharm Sin B 2014; 4:266-9. [PMID: 26579394 PMCID: PMC4629081 DOI: 10.1016/j.apsb.2014.06.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Revised: 06/11/2014] [Accepted: 06/18/2014] [Indexed: 12/12/2022] Open
Abstract
HCV genotypes have been documented in clinical practice. The aim of this study was to determine the replication priority of different HCV genotypes in a Chinese HCV positive cohort. Serum samples from 491 apparently healthy Chinese blood donors testing positive for HCV antibodies and naive to antiviral drug therapy were tested. Genotyping analysis showed that genotypes 1b and 2a were predominant and accounted for 77.6% of the HCV infections. Among the genotype groups, individuals infected with genotype 2a had an HCV RNA viral load (108 copies/mL) about 200-fold (lg, 2.3) greater than those infected with other genotypes (104–105 copies/mL) indicating a replication priority of genotype 2a. However, there was no correlation between HCV genotype and antibody response suggesting that the amplification advantage of genotype 2a results from a favorable interaction with the host cellular environment. In conclusion, HCV genotypes 1b and 2a are the predominant genotypes in China and genotype 2a possesses a significant replication priority compared with the other genotypes. This suggests the existence of host cellular factors that may act as drug-targets for entirely clearing HCV infection in the future.
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28
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Ireton RC, Gale M. Pushing to a cure by harnessing innate immunity against hepatitis C virus. Antiviral Res 2014; 108:156-64. [PMID: 24907428 DOI: 10.1016/j.antiviral.2014.05.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Revised: 05/08/2014] [Accepted: 05/23/2014] [Indexed: 02/08/2023]
Abstract
Hepatitis C virus (HCV) causes 350,000 deaths and infects at least 3million people worldwide every year. Currently no vaccine has been developed. Direct-acting antiviral (DAA) drugs with high efficacy for suppressing HCV infection have recently been introduced into the clinic. While DAAs initially required combination therapy with type-1 interferon (IFN) administration for full efficacy and to avoid viral resistance to treatment, new DAA combinations show promise as an IFN-free regimen. However, IFN-free DAA therapy is in its infancy, still to be proven and today is cost-prohibitive for the patient. A major goal in HCV therapy to remove or replace IFN with DAAs or an alternative therapeutic to render virologic response with continued virus sensitivity to DAAs, thus facilitating a cure for infection. Recent advances in our understanding of innate immune responses to HCV have identified new therapeutic targets to combat HCV infection. We discuss how the targeting of innate immune response factors can be harnessed with DAAs to produce new generations of DAA-based HCV therapeutics. This article forms part of a symposium in Antiviral Research on "Hepatitis C: next steps toward global eradication."
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Affiliation(s)
- Reneé C Ireton
- Center for the Study of Innate Immunity to Hepatitis C Virus, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195, United States.
| | - Michael Gale
- Center for the Study of Innate Immunity to Hepatitis C Virus, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195, United States.
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29
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Fu J, Wei J. Molecular dynamics study on drug resistance mechanism of HCV NS3/4A protease inhibitor: BI201335. MOLECULAR SIMULATION 2014. [DOI: 10.1080/08927022.2014.917298] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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30
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Gouthamchandra K, Kumar A, Shwetha S, Mukherjee A, Chandra M, Ravishankar B, Khaja MN, Sadhukhan PC, Das S. Serum proteomics of hepatitis C virus infection reveals retinol-binding protein 4 as a novel regulator. J Gen Virol 2014; 95:1654-1667. [PMID: 24784414 DOI: 10.1099/vir.0.062430-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Persistent infection of hepatitis C virus (HCV) can lead to liver cirrhosis and hepatocellular carcinoma, which are currently diagnosed by invasive liver biopsy. Approximately 15-20 % of cases of chronic liver diseases in India are caused by HCV infection. In North India, genotype 3 is predominant, whereas genotype 1 is predominant in southern parts of India. The aim of this study was to identify differentially regulated serum proteins in HCV-infected Indian patients (genotypes 1 and 3) using a two-dimensional electrophoresis approach. We identified eight differentially expressed proteins by MS. Expression levels of one of the highly upregulated proteins, retinol-binding protein 4 (RBP4), was validated by ELISA and Western blotting in two independent cohorts. We also confirmed our observation in the JFH1 infectious cell culture system. Interestingly, the HCV core protein enhanced RBP4 levels and partial knockdown of RBP4 had a positive impact on HCV replication, suggesting a possible role for this cellular protein in regulating HCV infection. Analysis of RBP4-interacting partners using a bioinformatic approach revealed novel insights into the possible involvement of RBP4 in HCV-induced pathogenesis. Taken together, this study provided information on the proteome profile of the HCV-infected Indian population, and revealed a link between HCV infection, RBP4 and insulin resistance.
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Affiliation(s)
- K Gouthamchandra
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560 012, India
| | - Anuj Kumar
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560 012, India
| | - Shivaprasad Shwetha
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560 012, India
| | - Anirban Mukherjee
- ICMR Virus Unit, Kolkata, ID & BG Hospital Campus, GB-4 (East Wing) 1st Floor, 57, Dr Suresh Chandra Banerjee Road, Beliaghata, Kolkata 700010, India
| | - Madhavi Chandra
- Bioviz Technologies Pvt Ltd, Sagar Society, Road No. 2, Banjara Hills, Hyderabad 500 034, India
| | | | - M N Khaja
- Bioviz Technologies Pvt Ltd, Sagar Society, Road No. 2, Banjara Hills, Hyderabad 500 034, India
| | - Provash Chandra Sadhukhan
- ICMR Virus Unit, Kolkata, ID & BG Hospital Campus, GB-4 (East Wing) 1st Floor, 57, Dr Suresh Chandra Banerjee Road, Beliaghata, Kolkata 700010, India
| | - Saumitra Das
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560 012, India
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31
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Kim DW, Lee SA, Kim H, Won YS, Kim BJ. Naturally occurring mutations in the nonstructural region 5B of hepatitis C virus (HCV) from treatment-naïve Korean patients chronically infected with HCV genotype 1b. PLoS One 2014; 9:e87773. [PMID: 24489961 PMCID: PMC3906201 DOI: 10.1371/journal.pone.0087773] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Accepted: 12/30/2013] [Indexed: 12/29/2022] Open
Abstract
The nonstructural 5B (NS5B) protein of the hepatitis C virus (HCV) with RNA-dependent RNA polymerase (RdRp) activity plays a pivotal role in viral replication. Therefore, monitoring of its naturally occurring mutations is very important for the development of antiviral therapies and vaccines. In the present study, mutations in the partial NS5B gene (492 bp) from 166 quasispecies of 15 genotype-1b (GT) treatment-naïve Korean chronic patients were determined and mutation patterns and frequencies mainly focusing on the T cell epitope regions were evaluated. The mutation frequency within the CD8+ T cell epitopes was significantly higher than those outside the CD8+ T cell epitopes. Of note, the mutation frequency within predicted CD4+ T cell epitopes, a particular mutational hotspot in Korean patients was significantly higher than it was in patients from other areas, suggesting distinctive CD4+ T cell-mediated immune pressure against HCV infection in the Korean population. The mutation frequency in the NS5B region was positively correlated with patients with carrier-stage rather than progressive liver disease (chronic hepatitis, liver cirrhosis and hepatocellular carcinoma). Furthermore, the mutation frequency in four codons (Q309, A333, V338 and Q355) known to be related to the sustained virological response (SVR) and end-of treatment response (ETR) was also significantly higher in Korean patients than in patients from other areas. In conclusion, a high degree of mutation frequency in the HCV GT-1b NS5B region, particularly in the predicted CD4+ T cell epitopes, was found in Korean patients, suggesting the presence of distinctive CD4+ T cell pressure in the Korean population. This provides a likely explanation of why relatively high levels of SVR after a combined therapy of pegylated interferon (PEG-IFN) and ribavirin (RBV) in Korean chronic patients with GT-1b infections are observed.
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Affiliation(s)
- Dong-Won Kim
- Department of Biomedical Sciences, Microbiology and Immunology, and Liver Research Institute, College of Medicine, Seoul National University, Seoul, Korea
| | - Seoung-Ae Lee
- Department of Biomedical Sciences, Microbiology and Immunology, and Liver Research Institute, College of Medicine, Seoul National University, Seoul, Korea
| | - Hong Kim
- Department of Biomedical Sciences, Microbiology and Immunology, and Liver Research Institute, College of Medicine, Seoul National University, Seoul, Korea
| | - You-Sub Won
- Department of Biomedical Sciences, Microbiology and Immunology, and Liver Research Institute, College of Medicine, Seoul National University, Seoul, Korea
| | - Bum-Joon Kim
- Department of Biomedical Sciences, Microbiology and Immunology, and Liver Research Institute, College of Medicine, Seoul National University, Seoul, Korea
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Bukong TN, Kodys K, Szabo G. A Novel Human Radixin Peptide Inhibits Hepatitis C Virus Infection at the Level of Cell Entry. Int J Pept Res Ther 2014; 20:269-276. [PMID: 25379035 DOI: 10.1007/s10989-013-9390-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hepatitis C virus infection of hepatocytes is a multistep process involving the interaction between viral and host cell molecules. Recently, we identified ezrin-moesin-radixin proteins and spleen tyrosine kinase (SYK) as important host therapeutic targets for HCV treatment development. Previously, an ezrin hinge region peptide (Hep1) has been shown to exert anti-HCV properties in vivo, though its mechanism of action remains limited. In search of potential novel inhibitors of HCV infection and their functional mechanism we analyzed the anti-HCV properties of different human derived radixin peptides. Sixteen different radixin peptides were derived, synthesized and tested. Real-time quantitative PCR, cell toxicity assay, immuno-precipitation/western blot analysis and computational resource for drug discovery software were used for experimental analysis. We found that a human radixin hinge region peptide (Peptide1) can specifically block HCV J6/JFH-1 infection of Huh7.5 cells. Peptide 1 had no cell toxicity or intracellular uptake into Huh7.5 cells. Mechanistically, the anti-HCV activity of Peptide 1 extended to disruption of HCV engagement of CD81 thereby blocking downstream SYK activation, which we have recently demonstrated to be important for effective HCV infection of target hepatocytes. Our findings highlight a novel functional class of anti-HCV agents that can inhibit HCV infection, most likely by disrupting vital viral-host signaling interactions at the level of virus entry.
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Affiliation(s)
- Terence N Bukong
- Department of Medicine, University of Massachusetts Medical School, LRB208, 364 Plantation Street, Worcester, MA 01605, USA
| | - Karen Kodys
- Department of Medicine, University of Massachusetts Medical School, LRB208, 364 Plantation Street, Worcester, MA 01605, USA
| | - Gyongyi Szabo
- Department of Medicine, University of Massachusetts Medical School, LRB208, 364 Plantation Street, Worcester, MA 01605, USA
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Ravi S, Nasiri-Toosi M, Karimzadeh I, Khalili H, Ahadi-Barzoki M, Dashti-Khavidaki S. Pattern and associated factors of anti-hepatitis C virus treatment-induced adverse reactions. Expert Opin Drug Saf 2014; 13:277-86. [DOI: 10.1517/14740338.2014.866091] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Affiliation(s)
- Saeedeh Ravi
- Tehran University of Medical Sciences, Department of Clinical Pharmacy, Faculty of Pharmacy, Postal Code: 1417614411, P.O. Box: 14155/6451, Tehran, IR Iran ;
- Islamic Azad University, Department of Clinical Pharmacy, Pharmaceutical Sciences Branch, Tehran, IR Iran
| | - Mohsen Nasiri-Toosi
- Tehran University of Medical Sciences, Department of Gastroenterology, Faculty of Medicine, Tehran, IR Iran
| | - Iman Karimzadeh
- Tehran University of Medical Sciences, Department of Clinical Pharmacy, Faculty of Pharmacy, Postal Code: 1417614411, P.O. Box: 14155/6451, Tehran, IR Iran ;
| | - Hossein Khalili
- Tehran University of Medical Sciences, Department of Clinical Pharmacy, Faculty of Pharmacy, Postal Code: 1417614411, P.O. Box: 14155/6451, Tehran, IR Iran ;
| | - Mehdi Ahadi-Barzoki
- Zanjan University of Medical Sciences, Department of Clinical Pharmacy, Faculty of Pharmacy, Zanjan, IR Iran
| | - Simin Dashti-Khavidaki
- Tehran University of Medical Sciences, Department of Clinical Pharmacy, Faculty of Pharmacy, Postal Code: 1417614411, P.O. Box: 14155/6451, Tehran, IR Iran ;
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34
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Jiao P, Xue W, Shen Y, Jin N, Liu H. Understanding the drug resistance mechanism of hepatitis C virus NS5B to PF-00868554 due to mutations of the 423 site: a computational study. MOLECULAR BIOSYSTEMS 2014; 10:767-77. [DOI: 10.1039/c3mb70498j] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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35
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Activation and evasion of antiviral innate immunity by hepatitis C virus. J Mol Biol 2013; 426:1198-209. [PMID: 24184198 DOI: 10.1016/j.jmb.2013.10.032] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Revised: 10/22/2013] [Accepted: 10/23/2013] [Indexed: 02/08/2023]
Abstract
Hepatitis C virus (HCV) chronically infects 130-170 million people worldwide and is a major public health burden. HCV is an RNA virus that infects hepatocytes within liver, and this infection is sensed as non-self by the intracellular innate immune response to program antiviral immunity to HCV. HCV encodes several strategies to evade this antiviral response, and this evasion of innate immunity plays a key role in determining viral persistence. This review discusses the molecular mechanisms of how the intracellular innate immune system detects HCV infection, including how HCV pathogen-associated molecular patterns are generated during infection and where they are recognized as foreign by the innate immune system. Further, this review highlights the key innate immune evasion strategies used by HCV to establish persistent infection within the liver, as well as how host genotype influences the outcome of HCV infection. Understanding these HCV-host interactions is key in understanding how to target HCV during infection and for the design of more effective HCV therapies at the immunological level.
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36
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Song WH, Liu MM, Zhong DW, Zhu YL, Bosscher M, Zhou L, Ye DY, Yuan ZH. Tetrazole and triazole as bioisosteres of carboxylic acid: Discovery of diketo tetrazoles and diketo triazoles as anti-HCV agents. Bioorg Med Chem Lett 2013; 23:4528-31. [DOI: 10.1016/j.bmcl.2013.06.045] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Revised: 06/12/2013] [Accepted: 06/15/2013] [Indexed: 02/02/2023]
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37
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Zhu Z, Mathahs MM, Schmidt WN. Restoration of type I interferon expression by heme and related tetrapyrroles through inhibition of NS3/4A protease. J Infect Dis 2013; 208:1653-63. [PMID: 23901085 DOI: 10.1093/infdis/jit338] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Tetrapyrrole substrates and products of heme oxygenase are potent inhibitors of hepatitis C virus (HCV) replication. It is not clear whether this occurs through primary induction of type I interferon (IFN), inhibition of viral NS3/4A protease, or a combination of these mechanisms. We studied the antiviral actions of tetrapyrroles and their potential influence on type I IFN induction. METHODS The effects of tetrapyrrole on NS3/4A protease activity and type I IFN induction were assessed in HCV-permissive cells, replicons, or human embryonic kidney (HEK) 293 cells transfected with NS3/4A protease. Activation of innate immune signaling was determined after transfection of double-strand surrogate nucleic acid antigens or infection with defined sequence HCV cell culture (HCVcc) RNA. RESULTS Tetrapyrroles failed to directly induce IFN expression at concentrations that inhibited HCV replication and NS3/4A protease activity. However, they potently restored IFN induction after attenuation with NS3/4A protease, a process accompanied by preservation of the adapter protein, mitochondrial antiviral signaling protein, nuclear localization of IFN regulatory factor 3, and augmentation of IFN-stimulated gene products. CONCLUSIONS Tetrapyrroles do not directly induce IFN, but they dramatically restore type I IFN signaling pathway after attenuation with NS3/4A protease. They show immunomodulatory as well as antiprotease activity and may be useful for treatment of HCV infection.
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Affiliation(s)
- Zhaowen Zhu
- Department of Internal Medicine and Research Service, Veterans Affairs Medical Center
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Horner SM, Gale M. Regulation of hepatic innate immunity by hepatitis C virus. Nat Med 2013; 19:879-88. [PMID: 23836238 PMCID: PMC4251871 DOI: 10.1038/nm.3253] [Citation(s) in RCA: 220] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2013] [Accepted: 05/30/2013] [Indexed: 02/08/2023]
Abstract
Hepatitis C virus (HCV) is a global public health problem involving chronic infection of the liver, which can cause liver disease and is linked with liver cancer. Viral innate immune evasion strategies and human genetic determinants underlie the transition of acute HCV infection to viral persistence and the support of chronic infection. Host genetic factors, such as sequence polymorphisms in IFNL3, a gene in the host interferon system, can influence both the outcome of the infection and the response to antiviral therapy. Recent insights into how HCV regulates innate immune signaling within the liver reveal a complex interaction of patient genetic background with viral and host factors of innate immune triggering and control that imparts the outcome of HCV infection and immunity.
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Affiliation(s)
- Stacy M Horner
- Department of Immunology, University of Washington, Seattle, Washington, USA
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Ahmed F. What about us? Recent advances in the treatment of chronic hepatitis C threaten to leave some parts of the world behind. J Viral Hepat 2013; 20:367-8. [PMID: 23565620 DOI: 10.1111/j.1365-2893.2012.01613.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Summary. Directly acting antiviral (DAA) agents are currently revolutionizing the treatment of chronic hepatitis C infection. The first generation of these agents have significant limitations including cost issues that are of particular concern in the developing world and a lack of efficacy in genotype 3 patients. Both of these concerns are of particular relevance in Pakistan.
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Affiliation(s)
- F Ahmed
- Division of Gastroenterology, The Aga Khan University, Karachi 75350, Pakistan.
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Nichols DB, Leão RAC, Basu A, Chudayeu M, de Moraes PDF, Talele TT, Costa PRR, Kaushik-Basu N. Evaluation of Coumarin and Neoflavone Derivatives as HCV NS5B Polymerase Inhibitors. Chem Biol Drug Des 2013; 81:607-14. [DOI: 10.1111/cbdd.12105] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2012] [Revised: 12/04/2012] [Accepted: 12/31/2012] [Indexed: 02/06/2023]
Affiliation(s)
- Daniel B. Nichols
- Department of Biochemistry and Molecular Biology; UMDNJ-New Jersey Medical School; 185 South Orange Avenue; Newark; NJ; 07103; USA
| | - Raquel A. C. Leão
- Laboratório de Química Bioorgânica, Núcleo de Pesquisas de Produtos Naturais; Centro de Ciências da Saúde; Bloco H; Universidade Federal do Rio de Janeiro; RJ; 21941-590; Brazil
| | - Amartya Basu
- Department of Biochemistry and Molecular Biology; UMDNJ-New Jersey Medical School; 185 South Orange Avenue; Newark; NJ; 07103; USA
| | - Maksim Chudayeu
- Department of Biochemistry and Molecular Biology; UMDNJ-New Jersey Medical School; 185 South Orange Avenue; Newark; NJ; 07103; USA
| | - Paula de F. de Moraes
- Laboratório de Química Bioorgânica, Núcleo de Pesquisas de Produtos Naturais; Centro de Ciências da Saúde; Bloco H; Universidade Federal do Rio de Janeiro; RJ; 21941-590; Brazil
| | - Tanaji T. Talele
- Department of Pharmaceutical Sciences; College of Pharmacy and Health Sciences; St. John's University; Queens; NY; 11439; USA
| | - Paulo R. R. Costa
- Laboratório de Química Bioorgânica, Núcleo de Pesquisas de Produtos Naturais; Centro de Ciências da Saúde; Bloco H; Universidade Federal do Rio de Janeiro; RJ; 21941-590; Brazil
| | - Neerja Kaushik-Basu
- Department of Biochemistry and Molecular Biology; UMDNJ-New Jersey Medical School; 185 South Orange Avenue; Newark; NJ; 07103; USA
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41
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AlMalki WH. HCV infection: an enigma, recent advances and new paradigms for its treatment. Future Virol 2013. [DOI: 10.2217/fvl.13.10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
HCV infection is a serious human liver health problem and has infected 200 million people worldwide. Persistent HCV infection can lead to chronic hepatitis C, which is a significant risk of serious hepatic diseases such as hepatic steatosis, hepatic fibrosis and hepatocellular carcinoma. The current standard-of-care options to treat HCV infection are limited, expensive and produce side effects in infected patients that often cause termination of the therapy. Recently, the approval of direct-acting antivirals represents a major breakthrough for the improvement of treatment strategies against chronic HCV infection. Similarly, the development of more effective, safe and well-tolerated interferon therapy is opening a new era in HCV therapeutics. Moreover, a new vaccine technology has been tested in mice for its therapeutic efficacy against the most conserved regions of the HCV genome. This review article will focus on the recent advances in HCV therapeutics and discuss new paradigms to develop the most convenient drugs and treatment strategies.
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Affiliation(s)
- Waleed Hassan AlMalki
- Department of Pharmacology & Toxicology, College of Pharmacy, Umm Al-Qura University, PO Box 13578, Makkah, Saudi Arabia
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Du NN, Peng ZG, Bi CW, Tang S, Li YH, Li JR, Zhu YP, Zhang JP, Wang YX, Jiang JD, Song DQ. N-substituted benzyl matrinic acid derivatives inhibit hepatitis C virus (HCV) replication through down-regulating host heat-stress cognate 70 (Hsc70) expression. PLoS One 2013; 8:e58675. [PMID: 23516533 PMCID: PMC3597726 DOI: 10.1371/journal.pone.0058675] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2012] [Accepted: 02/05/2013] [Indexed: 01/25/2023] Open
Abstract
Heat-stress cognate 70 (Hsc70) is a host factor that helps hepatitis C virus (HCV) to complete its life cycle in infected hepatocytes. Using Hsc70 as a target for HCV inhibition, a series of novel N-substituted benzyl matrinic/sophoridinic acid derivatives was synthesized and evaluated for their anti-HCV activity in vitro. Among these analogues, compound 7c possessing N-p-methylbenzyl afforded an appealing ability to inhibit HCV replication with SI value over 53. Furthermore, it showed a good oral pharmacokinetic profile with area-under-curve (AUC) of 13.4 µM·h, and a considerably good safety in oral administration in mice (LD50>1000 mg/kg). As 7c suppresses HCV replication via an action mode distinctly different from that of the marketed anti-HCV drugs, it has been selected as a new mechanism anti-HCV candidate for further investigation, with an advantage of no or decreased chance to induce drug-resistant mutations.
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Affiliation(s)
- Na-Na Du
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Zong-Gen Peng
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Chong-Wen Bi
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Sheng Tang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Ying-Hong Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Jian-Rui Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Yan-Ping Zhu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Jing-Pu Zhang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Yan-Xiang Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Jian-Dong Jiang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substance and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- * E-mail: (J-DJ); (D-QS)
| | - Dan-Qing Song
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
- * E-mail: (J-DJ); (D-QS)
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Cimini E, Bonnafous C, Sicard H, Vlassi C, D'Offizi G, Capobianchi MR, Martini F, Agrati C. In vivo interferon-alpha/ribavirin treatment modulates Vγ9Vδ2 T-cell function during chronic HCV infection. J Interferon Cytokine Res 2013; 33:136-41. [PMID: 23308376 DOI: 10.1089/jir.2012.0050] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
In chronic hepatitis C virus (HCV) infection, treatment failure and defective host immune response highly demand improved therapy strategies. Vγ9Vδ2 T-cells represent a good target for HCV immunotherapy, since phosphoantigen (PhAg)-activated Vγ9Vδ2 T-lymphocytes are able to inhibit subgenomic HCV replication by interferon (IFN)-γ release. A profound impairment of IFN-γ production by Vγ9Vδ2 T-cells during chronic HCV infection was previously shown. Interestingly, in vitro IFN-α partially restored Vγ9Vδ2 T-cells responsiveness to PhAg, by stabilizing IFN-γ-mRNA. To verify how in vivo IFN-α/ribavirin (RBV) treatment could affect Vγ9Vδ2 T-cells phenotype and responsiveness to PhAg in HCV-infected patients, 10 subjects underwent a longitudinal study before and after treatment. IFN-α/RBV therapy did not significantly modify Vγ9Vδ2 T-cell numbers and differentiation profile. Interestingly, Vγ9Vδ2 T-cell responsiveness remained unmodified until 3 weeks of therapy, but dropped after 1 month, suggesting that repeated in vivo IFN-α administration in the absence of T-cell receptor (TCR)-mediated signals results in Vγ9Vδ2 T-cell anergy. The present work defines the window of possible application of combined strategies targeting Vγ9Vδ2 T-cells during chronic HCV infection; specifically, the first 3 weeks from the beginning of treatment may represent the optimal time to target Vγ9Vδ2 T-cells in vivo, since their function in terms of IFN-γ production is preserved.
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Affiliation(s)
- Eleonora Cimini
- Cellular Immunology Laboratory, INMI L. Spallanzani, Rome, Italy
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González-Carmona MA, Quasdorff M, Vogt A, Tamke A, Yildiz Y, Hoffmann P, Lehmann T, Bartenschlager R, Engels JW, Kullak-Ublick GA, Sauerbruch T, Caselmann WH. Inhibition of hepatitis C virus RNA translation by antisense bile acid conjugated phosphorothioate modified oligodeoxynucleotides (ODN). Antiviral Res 2012; 97:49-59. [PMID: 23142319 DOI: 10.1016/j.antiviral.2012.10.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2012] [Revised: 10/26/2012] [Accepted: 10/28/2012] [Indexed: 01/22/2023]
Abstract
BACKGROUND The 5'-noncoding region (5'NCR) of the HCV-genome comprises an internal ribosome entry site essential for HCV-translation/replication. Phosphorothioate oligodeoxynucleotides (tS-ODN) complementary to this region can inhibit HCV-translation in vitro. In this study, bile acid conjugated tS-ODN were generated to increase cell-selective inhibition of 5'NCR-dependent HCV-translation. METHODS Different bile acid conjugated tS-ODN complementary to the HCV5'NCR were selected for their inhibitory potential in an in vitro transcription/translation assay. To analyze OATP (organic anion transporting polypeptides)-selective uptake of bile acid conjugated ODN, different hepatoma cells were stably transfected with the OATP1B1-transporter and primary human hepatocytes were used. An adenovirus encoding the HCV5'NCR fused to the luciferase gene (Ad-GFP-NCRluc) was generated to quantify 5'NCR-dependent HCV gene expression in OATP-overexpressing hepatoma cells and in vivo. RESULTS A 17mer phosphorothioate modified ODN (tS-ODN4_13) complementary to HCV5'NCR was able to inhibit 5'NCR-dependent HCV-translation in an in vitro transcription/translation test system by more than 90% and it was also effective in Huh7-cells containing the HCV subgenomic replicon. Conjugation to taurocholate (tS-ODN4_13T) significantly increased selective ODN uptake by primary human hepatocytes and by OATP1B1-expressing HepG2-cells compared to parental HepG2-cells. Correspondingly, tS-ODN4_13T significantly inhibited HCV gene expression in liver-derived OATP1B1-expressing HepG2- or CCL13-cells up to 70% compared to unconjugated tS-ODN and compared to mismatch taurocholate coupled tS-ODN. In vivo, tS-ODN4_13T showed also a trend to block 5'NCR-dependent HCV gene expression. CONCLUSIONS The tested taurocholate conjugated 17mer antisense ODN complementary to HCV5'NCV showed an increased and selective uptake by hepatocytes and liver-derived cells through OATP-mediated transport resulting in enhanced specific inhibition of HCV gene expression in vitro and in vivo. Thus, this novel approach may represent a promising strategy to improve antisense approaches with ODN in the control of hepatitis C infection.
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45
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Himmelsbach K, Hildt E. The kinase inhibitor Sorafenib impairs the antiviral effect of interferon α on hepatitis C virus replication. Eur J Cell Biol 2012; 92:12-20. [PMID: 23107224 DOI: 10.1016/j.ejcb.2012.09.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2012] [Revised: 09/08/2012] [Accepted: 09/14/2012] [Indexed: 02/07/2023] Open
Abstract
Recently, it was shown that the kinase inhibitor Sorafenib efficiently blocks HCV replication by inhibition of c-Raf. However, a longer treatment with higher doses of Sorafenib might be associated with adverse effects. Therefore, it was analysed whether a decreased dose of Sorafenib can be applied in combination with interferon α to obtain additive antiviral, but at the same time decreased adverse effects. However, Sorafenib abolishes the inhibitory effect of interferon α on HCV replication and vice versa. In order to reveal the underlying mechanisms, we observed that on the one hand IFNα activates c-Raf and thereby counteracts the inhibitory effect of Sorafenib on HCV replication that is based on the Sorafenib-dependent inhibition of c-Raf. On the other hand we found that the IFNα-induced PKR-phosphorylation depends on c-Raf. So, Sorafenib as a potent inhibitor of c-Raf prevents the IFNα-dependent PKR phosphorylation. Moreover, Sorafenib inhibits c-Raf-independent the phosphorylation of STAT1 resulting in an impaired induction of IFNα-dependent genes. Taken together, these data indicate that a combined application of Sorafenib and interferon α in order to obtain an antiviral effect is not useful since Sorafenib exerts an inhibitory effect on targets that are crucial for the transduction of interferon α-dependent antiviral response.
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46
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Schmidt WN, Mathahs MM, Zhu Z. Heme and HO-1 Inhibition of HCV, HBV, and HIV. Front Pharmacol 2012; 3:129. [PMID: 23060790 PMCID: PMC3463857 DOI: 10.3389/fphar.2012.00129] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2012] [Accepted: 06/18/2012] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus, human immunodeficiency virus, and hepatitis B virus are chronic viral infections that cause considerable morbidity and mortality throughout the world. In the decades following the identification and sequencing of these viruses, in vitro experiments demonstrated that heme oxygenase-1, its oxidative products, and related compounds of the heme oxygenase system inhibit replication of all 3 viruses. The purpose of this review is to critically evaluate and summarize the seminal studies that described and characterized this remarkable behavior. It will also discuss more recent work that discovered the antiviral mechanisms and target sites of these unique antiviral agents. In spite of the fact that these viruses are diverse pathogens with quite profound differences in structure and life cycle, it is significant that heme and related compounds show striking similarity for viral target sites across all three species. Collectively, these findings strongly indicate that we should move forward and develop heme and related tetrapyrroles into versatile antiviral agents that could be used therapeutically in patients with single or multiple viral infections.
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Affiliation(s)
- Warren N Schmidt
- Department of Internal Medicine and Research Service, Veterans Affairs Medical Center, University of Iowa Iowa City, IA, USA ; Department of Internal Medicine, Roy G. and Lucille A. Carver College of Medicine, University of Iowa Iowa City, IA, USA
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Golub AG, Gurukumar KR, Basu A, Bdzhola VG, Bilokin Y, Yarmoluk SM, Lee JC, Talele TT, Nichols DB, Kaushik-Basu N. Discovery of new scaffolds for rational design of HCV NS5B polymerase inhibitors. Eur J Med Chem 2012; 58:258-64. [PMID: 23127989 DOI: 10.1016/j.ejmech.2012.09.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2012] [Revised: 09/05/2012] [Accepted: 09/07/2012] [Indexed: 02/02/2023]
Abstract
Hepatitis C virus (HCV) NS5B polymerase is a key target for the development of anti-HCV drugs. Here we report on the identification of novel allosteric inhibitors of HCV NS5B through a combination of structure-based virtual screening and in vitro NS5B inhibition assays. One hundred and sixty thousand compounds from the Otava database were virtually screened against the thiazolone inhibitor binding site on NS5B (thumb pocket-2, TP-2), resulting in a sequential down-sizing of the library by 2.7 orders of magnitude to yield 59 NS5B non-nucleoside inhibitor (NNI) candidates. In vitro evaluation of the NS5B inhibitory activity of the 59 selected compounds resulted in a 14% hit rate, yielding 8 novel structural scaffolds. Of these, compound 1 bearing a 4-hydrazinoquinazoline scaffold was the most active (IC(50) = 16.0 μM). The binding site of all 8 NNIs was mapped to TP-2 of NS5B as inferred by a decrease in their inhibition potency against the M423T NS5B mutant, employed as a screen for TP-2 site binders. At 100 μM concentration, none of the eight compounds exhibited any cytotoxicity, and all except compound 8 exhibited between 40 and 60% inhibition of intracellular NS5B polymerase activity in BHK-NS5B-FRLuc reporter cells. These inhibitor scaffolds will form the basis for future optimization and development of more potent NS5B inhibitors.
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Affiliation(s)
- Andriy G Golub
- Department of Combinatorial Chemistry, Institute of Molecular Biology and Genetics of the National Academy of Sciences of Ukraine, 150 Zabolotnogo Street, 03143 Kyiv, Ukraine
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Agarwal A, Zhang B, Olek E, Robison H, Robarge L, Deshpande M. Rapid and sharp decline in HCV upon monotherapy with NS3 protease inhibitor, ACH-1625. Antivir Ther 2012; 17:1533-9. [PMID: 22976492 DOI: 10.3851/imp2359] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/03/2012] [Indexed: 12/17/2022]
Abstract
BACKGROUND ACH-1625 is a linear peptidomimetic inhibitor that non-covalently binds to HCV NS3 protease with high potency and specificity. Short-term monotherapy of HCV genotype-1 infection with ACH-1625 was found to be safe and resulted in ≥3.3 log(10) IU/ml mean viral load reduction. These viral load decay data were analysed to compare HCV dynamics with prior reports and estimate the antiviral efficiency of ACH-1625. METHODS Drug efficiency was estimated by analysing the viral decay following initiation of up to 5 days of monotherapy with ACH-1625 in 36 chronically infected HCV genotype-1 patients. During this monotherapy study, ACH-1625 was administered either twice-a-day for 4.5 days or once daily for 5 days at 5 different dose levels in 36 patients. RESULTS A sharp viral decay during the first 48 h following the initiation of ACH-1625 treatment afforded high drug efficiency estimates (≥0.9934). In addition, an increase in the estimated drug efficiency was observed with increasing ACH-1625 dose. The observed anti-HCV response was fairly uniform in this proof-of-concept study across the population of 36 patients. CONCLUSIONS Estimates of the treatment-independent viral kinetics parameters were consistent with prior reports and the estimated drug efficiency of ACH-1625 monotherapy was very high (≥0.9934) in fasted and fed states.
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Affiliation(s)
- Atul Agarwal
- Achillion Pharmaceuticals, Inc., New Haven, CT, USA.
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Alghamdi AS, Sanai FM, Ismail M, Alghamdi H, Alswat K, Alqutub A, Altraif I, Shah H, Alfaleh FZ. SASLT practice guidelines: management of hepatitis C virus infection. Saudi J Gastroenterol 2012; 18 Suppl:S1-32. [PMID: 23006491 PMCID: PMC3713589 DOI: 10.4103/1319-3767.101155] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Affiliation(s)
- Abdullah S. Alghamdi
- Department of Medicine, Gastroenterology Unit, King Fahad General Hospital, Jeddah, Saudi Arabia,Address for correspondence: Dr. Abdullah Saeed Alghamdi, Department of Medicine, King Fahad General Hospital, PO BOX 50505 (450), Jeddah, Saudi Arabia. E-mail:
| | - Faisal M. Sanai
- Hepatobiliary Sciences and Liver Transplantation, King Abdulaziz Medical City, and King Saud Bin Abdulaziz University for Health Sciences, National Guard Health Affairs,Liver Disease Research Center, National Plan for Science and Technology, King Saud University, Riyadh, Saudi Arabia
| | - Mona Ismail
- Department of Medicine, Division of Gastroenterology, King Fahad Hospital of the University, College of Medicine, University of Dammam, Dammam, Saudi Arabia
| | - Hamdan Alghamdi
- Hepatobiliary Sciences and Liver Transplantation, King Abdulaziz Medical City, and King Saud Bin Abdulaziz University for Health Sciences, National Guard Health Affairs
| | - Khalid Alswat
- Liver Disease Research Center, National Plan for Science and Technology, King Saud University, Riyadh, Saudi Arabia,Department of Medicine, Gastroenterology unit, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Adel Alqutub
- Department of Medicine, Gastroenterology Unit, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Ibrahim Altraif
- Hepatobiliary Sciences and Liver Transplantation, King Abdulaziz Medical City, and King Saud Bin Abdulaziz University for Health Sciences, National Guard Health Affairs
| | - Hemant Shah
- Division of Gastroenterology, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Faleh Z. Alfaleh
- Liver Disease Research Center, National Plan for Science and Technology, King Saud University, Riyadh, Saudi Arabia,Department of Medicine, Gastroenterology unit, College of Medicine, King Saud University, Riyadh, Saudi Arabia
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Vispo E, Rallon NI, Labarga P, Barreiro P, Benito JM, Soriano V. Different impact of IL28B polymorphisms on response to peginterferon-α plus ribavirin in HIV-positive patients infected with HCV subtypes 1a or 1b. J Clin Virol 2012; 55:58-61. [PMID: 22727259 DOI: 10.1016/j.jcv.2012.05.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2012] [Revised: 05/19/2012] [Accepted: 05/21/2012] [Indexed: 12/15/2022]
Abstract
BACKGROUND HCV subtype 1a has emerged as a predictor of poor response to triple hepatitis C therapy including boceprevir or telaprevir, which largely has been attributed to a lower resistance barrier in HCV-1a compared to -1b. OBJECTIVES We examined whether a lower efficacy of pegIFN/RBV on HCV-1a than HCV-1b could alternatively contribute to explain it. STUDY DESIGN All chronic hepatitis C patients who had completed a course of pegIFN/RBV therapy at our institution were examined. For this study we selected individuals that were IFN-naïve and had been successfully subtyped as 1a or 1b. Moreover, only HIV-coinfected patients were included as they represented a more uniform population in terms of demographics and treatment exposure at our institution. The IL28B rs12979860 alleles were typed using the 5' nuclease assay. RESULTS A total of 96 individuals were examined, 58 of whom harbored HCV-1a and 38 HCV-1b. IL28B allele distribution was as follows: 33 CC and 63 CT/TT. SVR was achieved by 64% of CC vs 30% of CT/TT patients (p=0.001). On the other hand, SVR was 53% in HCV-1b vs 34% in HCV-1a (p=0.08). Interestingly, the effect of IL28B variants on SVR was mainly recognized in HCV-1a (63% in CC vs 20% in CT/TT; p=0.001), being marginal on HCV-1b (64% in CC vs 46% in CT/TT; p=0.27). CONCLUSIONS The rate of SVR to pegIFN/RBV therapy tends to be lower in HIV-infected patients with chronic hepatitis C due to HCV-1a than HCV-1b; being the impact of IL28B variants significantly stronger on HCV-1a than HCV-1b.
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Affiliation(s)
- Eugenia Vispo
- Infectious Diseases Department, Hospital Carlos III, Madrid, Spain
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