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Ohlendorf V, Serfert Y, Buggisch P, Mauss S, Klinker H, Teuber G, Cornberg M, Tomasiewicz K, Wedemeyer H. Impact of distinct antiviral treatment regimens on the long-term outcome after HCV cure - Data from the German Hepatitis C-Registry (DHC-R). ZEITSCHRIFT FUR GASTROENTEROLOGIE 2025; 63:486-496. [PMID: 40360141 DOI: 10.1055/a-2543-5205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/15/2025]
Abstract
Direct-acting antiviral (DAA) regimens for the treatment of hepatitis C virus (HCV) infection are endowed with sustained virological response (SVR) rates >95%. However, HCV cure does not completely eliminate the risk of hepatocellular carcinoma (HCC) development and liver decompensation. The present study investigated the impact of the administered DAA regimen on clinical long-time outcomes after SVR.Matched-pair survival analyses of 5802 chronically HCV infected patients from the German Hepatitis C-Registry compared the incidence of liver-related events 2.5 years after SVR in patients receiving either sofosbuvir (SOF)-based treatment or NS3/NS4A-protease inhibitor (PI)-containing DAA regimens. Hypothesis driven logistic regression analyses were performed to identify independent predictors for the occurrence of liver-related events.Matched-pair survival analyses revealed a borderline significant difference in the incidence of liver-related endpoints (except of HCC development) in patients receiving SOF-based treatment (4.1%) compared to PI-containing DAA regimens (2.6%) 2.5 years after SVR (p=0.061). Numerically, a trend towards a benefit of PI-based DAA treatment was observed (PI 65 events vs SOF 102 events). Hypothesis driven logistic regression analyses could not confirm SOF-based treatment as an independent predictor for the occurrence of liver-related events after HCV cure (p=0.072, OR=0.670).The incidence of liver-related events 2.5 years after HCV cure did not differ significantly between SOF-based DAA treatment and PI-containing regimens. However, numerically a trend towards a benefit of PI-based DAA treatment was observed. Therefore, a minor effect of the applied DAA regimen on the long-term incidence of liver-related events cannot be excluded.
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Affiliation(s)
- Valerie Ohlendorf
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | | | - Peter Buggisch
- ifi-Institute for Interdisciplinary Medicine, Hamburg, Germany
| | - Stefan Mauss
- Center for HIV and Hepatogastroenterology, Duesseldorf, Germany
| | - Hartwig Klinker
- Division of Infectious Diseases, Department of Internal Medicine II, University of Würzburg Medical Center, Würzburg, Germany
| | | | - Markus Cornberg
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Centre for Individualised Infection Medicine (CiiM), Hannover, Germany
- German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Braunschweig, Germany
- Cluster of Excellence Resolving Infection Susceptibility (RESIST; EXC), Hannover Medical School, Hannover, Germany
| | | | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Leberstiftungs-GmbH Deutschland, Hannover, Germany
- German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Braunschweig, Germany
- Cluster of Excellence Resolving Infection Susceptibility (RESIST; EXC), Hannover Medical School, Hannover, Germany
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Zhou XJ, Good SS, Pietropaolo K, Huang Q, Moussa A, Hammond JM, Sommadossi JP. Bemnifosbuvir (BEM, AT-527), a novel nucleotide analogue inhibitor of the hepatitis C virus NS5B polymerase. Expert Opin Investig Drugs 2024; 33:9-17. [PMID: 38265202 DOI: 10.1080/13543784.2024.2305137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 01/10/2024] [Indexed: 01/25/2024]
Abstract
INTRODUCTION Chronic hepatitis C virus (HCV) persists as a public health concern worldwide. Consequently, optimizing HCV therapy remains an important objective. While current therapies are generally highly effective, advanced antiviral agents are needed to maximize cure rates with potentially shorter treatment durations in a broader patient population, particularly those patients with advanced diseases who remain difficult to treat. AREAS COVERED This review summarizes the in vitro anti-HCV activity, preclinical pharmacological properties of bemnifosbuvir (BEM, AT-527), a novel prodrug that is metabolically converted to AT-9010, the active guanosine triphosphate analogue that potently and selectively inhibits several viral RNA polymerases, including the HCV NS5B polymerase. Results from clinical proof-of-concept and phase 2 combination studies are also discussed. EXPERT OPINION BEM exhibits potent pan-genotype activity against HCV, and has favorable safety, and drug interaction profiles. BEM is approximately 10-fold more potent than sofosbuvir against HCV genotypes (GT) tested in vitro. When combined with a potent NS5A inhibitor, BEM is expected to be a promising once-daily oral antiviral for chronic HCV infection of all genotypes and fibrosis stages with potentially short treatment durations.
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Affiliation(s)
- Xiao-Jian Zhou
- Departments of Preclinical and Clinical Development, Atea Pharmaceuticals, Boston, MA, USA
| | - Steven S Good
- Departments of Preclinical and Clinical Development, Atea Pharmaceuticals, Boston, MA, USA
| | - Keith Pietropaolo
- Departments of Preclinical and Clinical Development, Atea Pharmaceuticals, Boston, MA, USA
| | - Qi Huang
- Departments of Preclinical and Clinical Development, Atea Pharmaceuticals, Boston, MA, USA
| | - Adel Moussa
- Departments of Preclinical and Clinical Development, Atea Pharmaceuticals, Boston, MA, USA
| | - Janet Mj Hammond
- Departments of Preclinical and Clinical Development, Atea Pharmaceuticals, Boston, MA, USA
| | - Jean-Pierre Sommadossi
- Departments of Preclinical and Clinical Development, Atea Pharmaceuticals, Boston, MA, USA
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Shehzadi K, Saba A, Yu M, Liang J. Structure-Based Drug Design of RdRp Inhibitors against SARS-CoV-2. Top Curr Chem (Cham) 2023; 381:22. [PMID: 37318607 DOI: 10.1007/s41061-023-00432-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 05/15/2023] [Indexed: 06/16/2023]
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic since 2019, spreading rapidly and posing a significant threat to human health and life. With over 6 billion confirmed cases of the virus, the need for effective therapeutic drugs has become more urgent than ever before. RNA-dependent RNA polymerase (RdRp) is crucial in viral replication and transcription, catalysing viral RNA synthesis and serving as a promising therapeutic target for developing antiviral drugs. In this article, we explore the inhibition of RdRp as a potential treatment for viral diseases, analysing the structural information of RdRp in virus proliferation and summarizing the reported inhibitors' pharmacophore features and structure-activity relationship profiles. We hope that the information provided by this review will aid in structure-based drug design and aid in the global fight against SARS-CoV-2 infection.
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Affiliation(s)
- Kiran Shehzadi
- Key Laboratory of Medical Molecule Science and Pharmaceutical Engineering, Ministry of Industry and Information Technology, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, 10081, China
| | - Afsheen Saba
- Key Laboratory of Medical Molecule Science and Pharmaceutical Engineering, Ministry of Industry and Information Technology, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, 10081, China
| | - Mingjia Yu
- Key Laboratory of Medical Molecule Science and Pharmaceutical Engineering, Ministry of Industry and Information Technology, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, 10081, China.
| | - Jianhua Liang
- Key Laboratory of Medical Molecule Science and Pharmaceutical Engineering, Ministry of Industry and Information Technology, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, 10081, China.
- Yangtze Delta Region Academy of Beijing Institute of Technology, Jiaxing, 314019, China.
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Younas S, Sumrin A, Hussain N, Bilal M. Identification of NS5B Resistance against SOFOSBUVIR in Hepatitis C Virus Genotype 3a, naive and treated Patients. J Appl Microbiol 2022; 133:2826-2834. [PMID: 35916643 DOI: 10.1111/jam.15754] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 07/28/2022] [Accepted: 07/29/2022] [Indexed: 11/29/2022]
Abstract
AIMS Pakistan has the second highest prevalence of HCV with genotype 3a (GT-3a) being the most frequently circulating genotype. Currently resistance associated substitutions (RASs) are a major challenge in HCV treatment with direct acting antivirals (DAAs). Sofosbuvir (SOF) is an FDA-approved NS5B nucleotide inhibitor. The aim of this study was to identify these RASs in the NS5B gene in naive and treated Pakistani HCV 3a isolates against SOF. METHODS AND RESULTS Blood samples were collected from anti-HCV positive patients, followed by HCV RNA isolation and real time PCR quantification. HCV positive patients were processed for HCV RNA genotyping, Patients with genotype 3a were processed for NS5B gene amplification and sequencing. GT-3a was the most prevalent genotype (62.2%). S282T was identified in 2 (8.7%) patients, C316Y/G/R in 3 (13%), V321A, and L320P in 1 (4.3%) each in SOF/RBV resistant patients. Variants of S282 were detected in 3 (13%) of SOF/RBV treated patients. While INF/RBV associated mutations were also analyzed, D244N, A333R, and A334E were identified in 2 (9.5%), 3 (14.2%), and 7 (33.3%) in treatment-naive and 15 (65.2%), 7 (30.4%), and 5 (21.7%) treated patients respectively. Q309R was observed only in one treatment experienced patients. Some substitutions were present at higher frequency in both groups like N307G, K304R, A272D and R345H, considered that they do not have any role in Sofosbuvir resistance. CONCLUSION It was concluded that Sofosbuvir RASs are present in Pakistani HCV GT-3a isolates, and they should be monitored carefully, especially in treatment-experienced patients, for further selection of treatment regimens. SIGNIFICANCE AND IMPACT OF STUDY HCV RASs have been studied very well across the world but there is scarcity of data regarding this topic in Pakistani population, this study provides data regarding prevalence of these RASs in Pakistani HCV isolates emphasizing the fact that these RASs must be carefully monitored before starting HCV treatment especially in treatment failure patients.
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Affiliation(s)
- Saima Younas
- Centre for Applied Molecular Biology (CAMB), University of the Punjab Lahore, Pakistan
| | - Aleena Sumrin
- Centre for Applied Molecular Biology (CAMB), University of the Punjab Lahore, Pakistan
| | - Nazim Hussain
- Centre for Applied Molecular Biology (CAMB), University of the Punjab Lahore, Pakistan
| | - Muhammad Bilal
- School of Life Science and Food Engineering, Huaiyin Institute of Technology, Huaian, China
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Hayes CN, Imamura M, Tanaka J, Chayama K. Road to elimination of HCV: Clinical challenges in HCV management. Liver Int 2022; 42:1935-1944. [PMID: 34967486 DOI: 10.1111/liv.15150] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 11/29/2021] [Accepted: 12/27/2021] [Indexed: 12/12/2022]
Abstract
Since its discovery in 1989, the road to a cure for hepatitis C virus (HCV) has been slow, but most patients can now expect to achieve a sustained virological response (SVR). With direct-acting antiviral (DAA) combination therapies such as glecaprevir/pibrentasvir and velpatasvir/sofosbuvir, 98% of patients successfully eradicate the virus, even if previous treatments failed or if resistance-associated substitutions (RASs) are present. Adverse events are rare or mild, and patients with compensated cirrhosis and other co-morbidities are often eligible for treatment. However, a small number of patients fail to eradicate the virus even after retreatment. The cause of failure is mainly due to emergence of NS5A P32 deletion mutants after initial DAA therapy in genotype 1b patients, although the reason is unknown for some patients. Alternative therapies that do not rely on NS5A inhibitors, such as sofosbuvir plus ribavirin, can be attempted in these patients. While scaled-up treatment efforts present a challenge, another problem is that many carriers are unaware of their infection. Long-term damage to the liver becomes irreversible, and patients who are not diagnosed in time can develop liver cancer or liver failure even after eliminating the virus. The long-term costs of treatment of advanced liver disease in undiagnosed patients relative to the immediate costs of DAA therapy should be considered. As no vaccine is yet available, eventual elimination of the virus requires identifying and treating undiagnosed cases and screening of high-risk populations such as injection drug users and men who have sex with men and female sex workers.
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Affiliation(s)
- C Nelson Hayes
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Junko Tanaka
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.,Department of Epidemiology, Infectious Disease Control and Prevention, Graduate school of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.,Collaborative Research Laboratory of Medical Innovation, Hiroshima University, Hiroshima, Japan.,RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
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Fernandes PO, Chagas MA, Rocha WR, Moraes AH. Non-structural protein 5 (NS5) as a target for antiviral development against established and emergent flaviviruses. Curr Opin Virol 2021; 50:30-39. [PMID: 34340199 DOI: 10.1016/j.coviro.2021.07.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 06/18/2021] [Accepted: 07/02/2021] [Indexed: 11/19/2022]
Abstract
Flaviviruses are among the most critical pathogens in tropical regions and cause a growing number of severe diseases in developing countries. The development of antiviral therapeutics is crucial for managing flavivirus outbreaks. Among the ten proteins encoded in the flavivirus RNA, non-structural protein 5, NS5, is a promising drug target. NS5 plays a fundamental role in flavivirus replication, viral RNA methylation, RNA polymerization, and host immune system evasion. Most of the NS5 inhibitor candidates target NS5 active sites. However, the similarity of NS5 activity sites with human enzymes can cause side effects. Identifying new allosteric sites in NS5 can contribute enormously to antiviral development. The NS5 structural characterization enabled exploring new regions, such as the residues involved in MTase-RdRp interaction, NS5 oligomerization, and NS5 interaction with other viral and host-cell proteins. Targeting NS5 critical interactions might lead to new compounds and overcomes the toxicity of current NS5-inhibitor candidates.
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Affiliation(s)
- Philipe O Fernandes
- Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, Brazil
| | - Marcelo A Chagas
- Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, Brazil
| | - Willian R Rocha
- Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, Brazil
| | - Adolfo H Moraes
- Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, Brazil; Department of NMR-based Structural Biology, Max-Planck Institute for Biophysical Chemistry, Am Fassberg 11, D-37077 Göttingen, Germany.
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7
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Cox RM, Sourimant J, Govindarajan M, Natchus MG, Plemper RK. Therapeutic targeting of measles virus polymerase with ERDRP-0519 suppresses all RNA synthesis activity. PLoS Pathog 2021; 17:e1009371. [PMID: 33621266 PMCID: PMC7935272 DOI: 10.1371/journal.ppat.1009371] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 03/05/2021] [Accepted: 02/10/2021] [Indexed: 12/20/2022] Open
Abstract
Morbilliviruses, such as measles virus (MeV) and canine distemper virus (CDV), are highly infectious members of the paramyxovirus family. MeV is responsible for major morbidity and mortality in non-vaccinated populations. ERDRP-0519, a pan-morbillivirus small molecule inhibitor for the treatment of measles, targets the morbillivirus RNA-dependent RNA-polymerase (RdRP) complex and displayed unparalleled oral efficacy against lethal infection of ferrets with CDV, an established surrogate model for human measles. Resistance profiling identified the L subunit of the RdRP, which harbors all enzymatic activity of the polymerase complex, as the molecular target of inhibition. Here, we examined binding characteristics, physical docking site, and the molecular mechanism of action of ERDRP-0519 through label-free biolayer interferometry, photoaffinity cross-linking, and in vitro RdRP assays using purified MeV RdRP complexes and synthetic templates. Results demonstrate that unlike all other mononegavirus small molecule inhibitors identified to date, ERDRP-0519 inhibits all phosphodiester bond formation in both de novo initiation of RNA synthesis at the promoter and RNA elongation by a committed polymerase complex. Photocrosslinking and resistance profiling-informed ligand docking revealed that this unprecedented mechanism of action of ERDRP-0519 is due to simultaneous engagement of the L protein polyribonucleotidyl transferase (PRNTase)-like domain and the flexible intrusion loop by the compound, pharmacologically locking the polymerase in pre-initiation conformation. This study informs selection of ERDRP-0519 as clinical candidate for measles therapy and identifies a previously unrecognized druggable site in mononegavirus L polymerase proteins that can silence all synthesis of viral RNA. The mononegavirus order contains major established and recently emerged human pathogens. Despite the threat to human health, antiviral therapeutics directed against this order remain understudied. The mononegavirus polymerase complex represents a promising drug target due to its central importance for both virus replication and viral mitigation of the innate host antiviral response. In this study, we have mechanistically characterized a clinical candidate small-molecule MeV polymerase inhibitor. The compound blocked all phosphodiester bond formation activity, a unique mechanism of action unlike all other known mononegavirus polymerase inhibitors. Photocrosslinking-based target site mapping demonstrated that this class-defining prototype inhibitor stabilizes a pre-initiation conformation of the viral polymerase complex that sterically cannot accommodate template RNA. Function-equivalent druggable sites exist in all mononegavirus polymerases. In addition to its direct anti-MeV impact, the insight gained in this study can therefore serve as a blueprint for indication spectrum expansion through structure-informed scaffold engineering or targeted drug discovery.
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Affiliation(s)
- Robert M. Cox
- Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, United States of America
| | - Julien Sourimant
- Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, United States of America
| | - Mugunthan Govindarajan
- Emory Institute for Drug Development, Emory University, Atlanta, Georgia, United States of America
| | - Michael G. Natchus
- Emory Institute for Drug Development, Emory University, Atlanta, Georgia, United States of America
| | - Richard K. Plemper
- Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, United States of America
- * E-mail:
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8
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Ramesh D, Vijayakumar BG, Kannan T. Advances in Nucleoside and Nucleotide Analogues in Tackling Human Immunodeficiency Virus and Hepatitis Virus Infections. ChemMedChem 2021; 16:1403-1419. [PMID: 33427377 DOI: 10.1002/cmdc.202000849] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Indexed: 12/13/2022]
Abstract
Nucleoside and nucleotide analogues are structurally similar antimetabolites and are promising small-molecule chemotherapeutic agents against various infectious DNA and RNA viruses. To date, these analogues have not been documented in-depth as anti-human immunodeficiency virus (HIV) and anti-hepatitis virus agents, these are at various stages of testing ranging from pre-clinical, to those withdrawn from trials, or those that are approved as drugs. Hence, in this review, the importance of these analogues in tackling HIV and hepatitis virus infections is discussed with a focus on the viral genome and the mechanism of action of these analogues, both in a mutually exclusive manner and their role in HIV/hepatitis coinfection. This review encompasses nucleoside and nucleotide analogues from 1987 onwards, starting with the first nucleoside analogue, zidovudine, and going on to those in current clinical trials and even the drugs that have been withdrawn. This review also sheds light on the prospects of these nucleoside analogues in clinical trials as a treatment option for the COVID-19 pandemic.
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Affiliation(s)
- Deepthi Ramesh
- Department of Chemistry, Pondicherry University, Kalapet, Puducherry, 605014, India
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9
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Yi D, Li Q, Pang L, Wang Y, Zhang Y, Duan Z, Liang C, Cen S. Identification of a Broad-Spectrum Viral Inhibitor Targeting a Novel Allosteric Site in the RNA-Dependent RNA Polymerases of Dengue Virus and Norovirus. Front Microbiol 2020; 11:1440. [PMID: 32670253 PMCID: PMC7330483 DOI: 10.3389/fmicb.2020.01440] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Accepted: 06/04/2020] [Indexed: 12/23/2022] Open
Abstract
All RNA viruses encode the RNA-dependent RNA polymerase (RdRp) which replicates and transcribes viral RNA. This essential viral enzyme does not exist in mammalian cells, thus presents a main target for the development of antiviral drugs with potential pan-antiviral activity. In this study, we take advantage of the structurally equivalent site in the dengue virus (DENV) RdRp, the N-pocket, and in the human norovirus (hNV) RdRp, the B-site, and performed a parallel structure-based virtual screening to discover compounds that can inhibit the RdRps of both hNV and DENV. We successfully identified a small molecule called Entrectinib (RAI-13) as a potent inhibitor of both hNV and DENV infection. Specifically, RAI-13 binds directly to hNV and DENV RdRps, effectively inhibits the polymerase activity in the in vitro biochemical assays, and exhibits does-responsive inhibition of murine norovirus (MNV) and DENV2 infection with IC50 values of 2.01 and 2.43 μM, respectively. Most promisingly, RAI-13 inhibits hepatitis C virus (HCV) infection by 95% at the 2 μM concentration. We have therefore discovered a small molecule compound that targets an allosteric site that is shared by different viral RdRps and strongly inhibits multiple pathogenic RNA viruses, thus holding the potential of being developed into a broad-spectrum antiviral drug.
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Affiliation(s)
- Dongrong Yi
- Department of Immunology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing, China
| | - Quanjie Li
- Department of Immunology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing, China
| | - Lili Pang
- National Institute for Viral Disease Control & Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Yujia Wang
- Department of Immunology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing, China
| | - Yongxin Zhang
- Department of Immunology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing, China
| | - Zhaojun Duan
- National Institute for Viral Disease Control & Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Chen Liang
- Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada
| | - Shan Cen
- Department of Immunology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing, China.,CAMS Key Laboratory of Antiviral Drug Research, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
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10
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Fadl N, Salem TZ. Hepatitis C genotype 4: A report on resistance-associated substitutions in NS3, NS5A, and NS5B genes. Rev Med Virol 2020; 30:e2120. [PMID: 32478480 DOI: 10.1002/rmv.2120] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 05/04/2020] [Accepted: 05/06/2020] [Indexed: 12/20/2022]
Abstract
AUTHOR CONTRIBUTION FN performed the literature review and wrote the manuscript; STZ coauthored, edited, and reviewed the manuscript. ABSTRACT Treatment response in Hepatitis C virus (HCV) has generated varied effects in patients. Recently, nonresponsive and relapse patients related to host and genotype variabilities have been reported in clinical trials. However, these trials included minimal sample sizes of patients with genotype 4, the most prevalent genotype in Egypt and the Middle East, compared with genotypes 1 and 2. The genetic variabilities that have been detected within the HCV genes, especially the ones associated with genotype 4, and are linked to treatment response, will be the focus of this review with emphasis on direct acting antiviral agents. In addition, the major studies and clinical trials performed globally and their inclusivity of genotype 4 are reported. This review also delineates future study areas and missing data that need further investigation when it comes to genotype 4.
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Affiliation(s)
- Nahla Fadl
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, Egypt
| | - Tamer Z Salem
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, Egypt.,Department of Microbial Genetics, AGERI, ARC, Giza, Egypt
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Abstract
Hepatitis C virus represents a global pathogen of human health significance. In the space of less than three decades, we have witnessed the discovery of the virus, a growing understanding of the structure and biology of the viral-encoded proteins and their interaction with the host cell and the sequencing of the viral genome. Most importantly, we have moved from early therapeutic strategies aimed at crude boosting of host anti-viral immunity, limited by side effects and with poor response rates, to therapies that directly exploit our understanding of viral biology. In this review, we discuss the significance of the virus, its' discovery and outline the advances in the molecular characterisation of the virus, before setting these within the context of contemporary and emerging therapeutic strategies as well as viral resistance mechanisms.
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12
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Zając M, Muszalska I, Sobczak A, Dadej A, Tomczak S, Jelińska A. Hepatitis C - New drugs and treatment prospects. Eur J Med Chem 2019; 165:225-249. [PMID: 30685524 DOI: 10.1016/j.ejmech.2019.01.025] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 01/11/2019] [Accepted: 01/11/2019] [Indexed: 12/19/2022]
Abstract
Hepatitis C virus (HCV) affects approx. 3% of the world's population and accounts for ca 300 000 deaths per year. 80% of individuals with HCV develop chronic symptoms which, when untreated, may cause cirrhosis (27%) or hepatocellular carcinoma (25%). The hepatitis C virus is a (+)ssRNA enveloped virus of the family Flaviviridae. Seven major HCV genotypes and their subtypes (a, b) have been identified. In the 1990s, interferons alpha-2 were used in the treatment of HCV and in the next decade HCV therapy was based on pegylated interferon alpha-2 in combination with ribavirin. Since 2011, interferons alpha, DNA and RNA polymerase inhibitors, NS3/4A RNA protease inhibitors, NS5 RNA serine protease inhibitors, NS5B RNA polymerase inhibitors have been approved for clinical use. Monotherapy is avoided in medication due to rapidly developing viral resistance. A total of 113 papers were included comprising original publications and reviews. The paper reviews the molecular targets and chemical structures of drugs used in HCV treatment. Indications and contraindications for anti-HCV drugs are also discussed together with application regimens.
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Affiliation(s)
- Marianna Zając
- Poznan University of Medicinal Sciences, Department of Pharmaceutical Chemistry, Grunwaldzka Str. 6, 60-780, Poznań, Poland
| | - Izabela Muszalska
- Poznan University of Medicinal Sciences, Department of Pharmaceutical Chemistry, Grunwaldzka Str. 6, 60-780, Poznań, Poland.
| | - Agnieszka Sobczak
- Poznan University of Medicinal Sciences, Department of Pharmaceutical Chemistry, Grunwaldzka Str. 6, 60-780, Poznań, Poland
| | - Adrianna Dadej
- Poznan University of Medicinal Sciences, Department of Pharmaceutical Chemistry, Grunwaldzka Str. 6, 60-780, Poznań, Poland
| | - Szymon Tomczak
- Poznan University of Medicinal Sciences, Department of Pharmaceutical Chemistry, Grunwaldzka Str. 6, 60-780, Poznań, Poland
| | - Anna Jelińska
- Poznan University of Medicinal Sciences, Department of Pharmaceutical Chemistry, Grunwaldzka Str. 6, 60-780, Poznań, Poland
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13
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Mahboubi Rabbani SMI, Vahabpour R, Hajimahdi Z, Zarghi A. Design, Synthesis, Molecular Modeling Studies and Biological Evaluation of N'-Arylidene-6-(benzyloxy)-4-oxo-1,4-dihydroquinoline-3-carbohydrazide Derivatives as Novel Anti-HCV Agents. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2019; 18:1790-1802. [PMID: 32184846 PMCID: PMC7059030 DOI: 10.22037/ijpr.2019.112186.13586] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
HCV-induced hepatitis is one of the most debilitating diseases. The limited number of anti-HCV drugs and drug-resistance necessitate developing of new scaffolds with different mode of actions. HCV non-structural protein 5B (NS5B) is an attractive target for development of novel inhibitors of HCV replication. In this paper, new N'-arylidene-6-(benzyloxy)-4-oxo-1,4-dihydroquinoline-3-carbohydrazide derivatives were designed based on the pharmacophores of HCV NS5B active site binding inhibitors. Designed compounds were synthesized and evaluated for their inhibitory activities in a cell-based HCV replicon system assay. Among tested compounds, compounds 18 and 20 were found to be the most active (EC50 = 35 and 70 µM, respectively) with good selectivity index (SI > 2) in the corresponding series. Molecular modeling studies showed that the designed compounds are capable of forming key coordination with the two magnesium ions as well as interactions with other key residues at the active site of HCV NS5B.
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Affiliation(s)
| | - Rouhollah Vahabpour
- Department of Medical Lab Technology, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Zahra Hajimahdi
- Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Afshin Zarghi
- Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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14
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Ashraf MU, Iman K, Khalid MF, Salman HM, Shafi T, Rafi M, Javaid N, Hussain R, Ahmad F, Shahzad-Ul-Hussan S, Mirza S, Shafiq M, Afzal S, Hamera S, Anwar S, Qazi R, Idrees M, Qureshi SA, Chaudhary SU. Evolution of efficacious pangenotypic hepatitis C virus therapies. Med Res Rev 2018; 39:1091-1136. [PMID: 30506705 DOI: 10.1002/med.21554] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 10/11/2018] [Accepted: 10/11/2018] [Indexed: 12/12/2022]
Abstract
Hepatitis C compromises the quality of life of more than 350 million individuals worldwide. Over the last decade, therapeutic regimens for treating hepatitis C virus (HCV) infections have undergone rapid advancements. Initially, structure-based drug design was used to develop molecules that inhibit viral enzymes. Subsequently, establishment of cell-based replicon systems enabled investigations into various stages of HCV life cycle including its entry, replication, translation, and assembly, as well as role of host proteins. Collectively, these approaches have facilitated identification of important molecules that are deemed essential for HCV life cycle. The expanded set of putative virus and host-encoded targets has brought us one step closer to developing robust strategies for efficacious, pangenotypic, and well-tolerated medicines against HCV. Herein, we provide an overview of the development of various classes of virus and host-directed therapies that are currently in use along with others that are undergoing clinical evaluation.
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Affiliation(s)
- Muhammad Usman Ashraf
- Biomedical Informatics Research Laboratory, Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan.,Virology Laboratory, Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Kanzal Iman
- Biomedical Informatics Research Laboratory, Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan
| | - Muhammad Farhan Khalid
- Biomedical Informatics Research Laboratory, Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan.,Department of Biomedical Engineering, University of Engineering and Technology, Lahore, Pakistan
| | - Hafiz Muhammad Salman
- Biomedical Informatics Research Laboratory, Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan.,Plant Biotechnology Laboratory, Institute of Agricultural Sciences, University of the Punjab, Lahore, Pakistan
| | - Talha Shafi
- Biomedical Informatics Research Laboratory, Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan
| | - Momal Rafi
- Department of Statistics, University of Gujrat, Gujrat, Pakistan
| | - Nida Javaid
- Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan
| | - Rashid Hussain
- Biomedical Informatics Research Laboratory, Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan
| | - Fayyaz Ahmad
- Department of Statistics, University of Gujrat, Gujrat, Pakistan
| | | | - Shaper Mirza
- Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan
| | - Muhammad Shafiq
- Plant Biotechnology Laboratory, Institute of Agricultural Sciences, University of the Punjab, Lahore, Pakistan
| | - Samia Afzal
- Virology Laboratory, Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Sadia Hamera
- Department of Plant Genetics, Institute of Life Sciences, University of Rostock, Germany
| | - Saima Anwar
- Department of Biomedical Engineering, University of Engineering and Technology, Lahore, Pakistan
| | - Romena Qazi
- Department of Pathology, Shaukat Khanum Memorial Cancer Hospital & Research Centre, Lahore, Pakistan
| | - Muhammad Idrees
- Virology Laboratory, Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.,Hazara University, Mansehra, Pakistan
| | - Sohail A Qureshi
- Institute of Integrative Biosciences, CECOS-University of Information Technology and Emerging Sciences, Peshawar, Pakistan
| | - Safee Ullah Chaudhary
- Biomedical Informatics Research Laboratory, Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan
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15
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Liu H, Dai X, He S, Brockunier L, Marcantonio K, Ludmerer SW, Li F, Feng KI, Nargund RP, Palani A. Design and evaluation of novel tetracyclic benzofurans as palm site allosteric inhibitors of HCV NS5B polymerase. Bioorg Med Chem Lett 2018; 29:126104. [PMID: 30389294 DOI: 10.1016/j.bmcl.2018.10.045] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 10/23/2018] [Accepted: 10/26/2018] [Indexed: 12/17/2022]
Abstract
Hepatitis C virus (HCV) NS5B polymerase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Several novel and potent HCV NS5B non-nucleoside inhibitors with unique tetracyclic bezonfuran-based structures were prepared and evaluated. Similar to clinical developmental compound MK-8876, N-linked (compounds 1 and 2) and C-linked (compounds 3 and 4) tetracyclic structures maintained broad spectrum anti-replicon potency profiles and demonstrated moderate to excellent oral bioavailability and pharmacokinetic parameters across the three preclinical animal species. To better understand the importance of tetracyclic structures related to pan genotypic potency profiles especially against clinically relevant GT1a variants, the teracycles with different ring size were prepared and in vitro evaluations suggested compounds with six number ring have better overall potency profiles.
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Affiliation(s)
- Hong Liu
- Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
| | - Xing Dai
- Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States
| | - Shuwen He
- Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States
| | - Linda Brockunier
- Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States
| | - Karen Marcantonio
- Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States
| | - Steven W Ludmerer
- Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States
| | - Fangbiao Li
- Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States
| | - Kung-I Feng
- Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States
| | - Ravi P Nargund
- Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States
| | - Anandan Palani
- Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States
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16
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Valade E, Kakuda TN, McClure MW, Westland C, Valenzuela B, Ouwerkerk-Mahadevan S, Perez-Ruixo JJ, Ackaert O. Population Pharmacokinetics of AL-335 and Its Two Main Metabolites (ALS-022399, ALS-022227) in Monotherapy and in Combination with Odalasvir and/or Simeprevir. AAPS JOURNAL 2018; 21:1. [PMID: 30377854 DOI: 10.1208/s12248-018-0272-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Accepted: 10/09/2018] [Indexed: 11/30/2022]
Abstract
The aim of the current study was to characterize the time course of plasma concentrations of AL-335 and its main metabolites (ALS-022399 and ALS-022227) after oral administration in healthy and hepatitis C virus (HCV)-infected subjects, in monotherapy as well as in combination with simeprevir and/or odalasvir. AL-335, ALS-022399, and ALS-022227 plasma concentrations from subjects receiving 800 mg of AL-335 orally once daily (qd) as monotherapy or in combination were pooled and analyzed using a nonlinear mixed effect modeling approach. The typical values (between subject variability) of AL-335 and ALS-022399 apparent linear clearances were 3300 L/h (33.9%) and 1910 L/h (30.0%), respectively. ALS-022227 elimination was characterized as a nonlinear process, with typical values of Vmax,ALS-022227 and Km,ALS-022227 estimated to be 84,799 ng/h (14.9%) and 450.2 ng/mL, respectively. AL-335 and ALS-022399 plasma concentrations were increased more than 2-fold in presence of simeprevir and/or odalasvir, while the effect on ALS-022227 plasma concentrations was limited. The effect of simeprevir and/or odalasvir might be explained by their capacity to inhibit P-glycoprotein. Internal evaluation confirmed that the population pharmacokinetic model developed was deemed appropriate to describe the time course of AL-335, ALS-022399, and ALS-022227 plasma concentrations and their associated variability in both healthy and HCV-infected subjects, as well as the interaction effect of simeprevir and/or odalasvir over AL-335 and its metabolites in healthy subjects. This model can be used as a starting point to evaluate drug-drug interaction processes in HCV-infected patients and support the development of a direct-acting antiviral (DAA) combination.
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Affiliation(s)
- Elodie Valade
- Janssen Research and Development, Global Clinical Pharmacology, Turnhoutseweg 30, B-2340, Beerse, Belgium
| | - Thomas N Kakuda
- Alios BioPharma, Inc., part of the Janssen Pharmaceutical Companies, South San Francisco, California, USA
| | - Matthew W McClure
- Alios BioPharma, Inc., part of the Janssen Pharmaceutical Companies, South San Francisco, California, USA
| | - Christopher Westland
- Alios BioPharma, Inc., part of the Janssen Pharmaceutical Companies, South San Francisco, California, USA
| | | | - Sivi Ouwerkerk-Mahadevan
- Janssen Research and Development, Global Clinical Pharmacology, Turnhoutseweg 30, B-2340, Beerse, Belgium
| | - Juan José Perez-Ruixo
- Janssen Research and Development, Global Clinical Pharmacology, Turnhoutseweg 30, B-2340, Beerse, Belgium
| | - Oliver Ackaert
- Janssen Research and Development, Global Clinical Pharmacology, Turnhoutseweg 30, B-2340, Beerse, Belgium.
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17
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Pretreatment Hepatitis C Virus NS5A/NS5B Resistance-Associated Substitutions in Genotype 1 Uruguayan Infected Patients. DISEASE MARKERS 2018; 2018:2514901. [PMID: 30186532 PMCID: PMC6112080 DOI: 10.1155/2018/2514901] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 05/30/2018] [Accepted: 06/10/2018] [Indexed: 12/18/2022]
Abstract
Hepatitis C Virus (HCV) infection treatment has dramatically changed with the advent of direct-acting antiviral agents (DAAs). However, the efficacy of DAAs can be attenuated by the presence of resistance-associated substitutions (RASs) before and after treatment. Indeed, RASs detected in DAA treatment-naïve HCV-infected patients could be useful for clinical management and outcome prediction. Although the frequency of naturally occurring HCV NS5A and NS5B RASs has been addressed in many countries, there are only a few reports on their prevalence in the South American region. The aim of this study was to investigate the presence of RASs to NS5A and NS5B inhibitors in a DAA treatment naïve cohort of Uruguayan patients infected with chronic hepatitis C and compare them with reports from other South American countries. Here, we found that naturally occurring substitutions conferring resistance to NS5A and NS5B inhibitors were present in 8% and 19.2%, respectively, of treatment-naïve HCV genotype 1 infected patients. Importantly, the baseline substitutions in NS5A and NS5B herein identified differ from the studies previously reported in Brazil. Furthermore, Uruguayan strains subtype 1a clustered within all major world clades, showing that HCV variants currently circulating in this country are characterized by a remarkable genetic diversity.
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18
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Simple In Vitro Assay To Evaluate the Incorporation Efficiency of Ribonucleotide Analog 5'-Triphosphates into RNA by Human Mitochondrial DNA-Dependent RNA Polymerase. Antimicrob Agents Chemother 2018; 62:AAC.01830-17. [PMID: 29180528 PMCID: PMC5786792 DOI: 10.1128/aac.01830-17] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 11/21/2017] [Indexed: 01/27/2023] Open
Abstract
There is a growing body of evidence suggesting that some ribonucleoside/ribonucleotide analogs may be incorporated into mitochondrial RNA by human mitochondrial DNA-dependent RNA polymerase (POLRMT) and disrupt mitochondrial RNA synthesis. An assessment of the incorporation efficiency of a ribonucleotide analog 5′-triphosphate by POLRMT may be used to evaluate the potential mitochondrial toxicity of the analog early in the development process. In this report, we provide a simple method to prepare active recombinant POLRMT. A robust in vitro nonradioactive primer extension assay was developed to assay the incorporation efficiency of ribonucleotide analog 5′-triphosphates. Our results show that many ribonucleotide analogs, including some antiviral compounds currently in various preclinical or clinical development stages, can be incorporated into newly synthesized RNA by POLRMT and that the incorporation of some of them can lead to chain termination. The discrimination (D) values of ribonucleotide analog 5′-triphosphates over those of natural ribonucleotide triphosphates (rNTPs) were measured to evaluate the incorporation efficiency of the ribonucleotide analog 5′-triphosphates by POLRMT. The discrimination values of natural rNTPs under the condition of misincorporation by POLRMT were used as a reference to evaluate the potential mitochondrial toxicity of ribonucleotide analogs. We propose the following criteria for the potential mitochondrial toxicity of ribonucleotide analogs based on D values: a safe compound has a D value of >105; a potentially toxic compound has a D value of >104 but <105; and a toxic compound has a D value of <104. This report provides a simple screening method that should assist investigators in designing ribonucleoside-based drugs having lower mitochondrial toxicity.
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19
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McComas CC, Palani A, Chang W, Holloway MK, Lesburg CA, Li P, Liverton N, Meinke PT, Olsen DB, Peng X, Soll RM, Ummat A, Wu J, Wu J, Zorn N, Ludmerer SW. Development of a New Structural Class of Broadly Acting HCV Non-Nucleoside Inhibitors Leading to the Discovery of MK-8876. ChemMedChem 2017; 12:1436-1448. [PMID: 28741898 DOI: 10.1002/cmdc.201700228] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 06/26/2017] [Indexed: 01/14/2023]
Abstract
Studies directed at developing a broadly acting non-nucleoside inhibitor of HCV NS5B led to the discovery of a novel structural class of 5-aryl benzofurans that simultaneously interact with both the palm I and palm II binding regions. An initial candidate was potent in vitro against HCV GT1a and GT1b replicons, and induced multi-log reductions in HCV viral load when orally dosed to chronic GT1 infected chimpanzees. However, in vitro potency losses against clinically relevant GT1a variants prompted a further effort to develop compounds with sustained potency across a broader array of HCV genotypes and mutants. Ultimately, a biology and medicinal chemistry collaboration led to the discovery of the development candidate MK-8876. MK-8876 demonstrated a pan-genotypic potency profile and maintained potency against clinically relevant mutants. It demonstrated moderate bioavailability in rats and dogs, but showed low plasma clearance characteristics consistent with once-daily dosing. Herein we describe the efforts which led to the discovery of MK-8876, which advanced into Phase 1 monotherapy studies for evaluation and characterization as a component of an all-oral direct-acting drug regimen for the treatment of chronic HCV infection.
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Affiliation(s)
- Casey C McComas
- Merck & Co. Inc., Kenilworth, NJ, USA.,Present address: International Discovery Service Unit, WuXi AppTec, Inc., 1690 Sumneytown Pike, Suite 150, Lansdale, PA, 19446, USA
| | - Anandan Palani
- Merck & Co. Inc., Kenilworth, NJ, USA.,Present address: International Discovery Service Unit, WuXi AppTec, Inc., 1690 Sumneytown Pike, Suite 150, Lansdale, PA, 19446, USA
| | | | - M Katharine Holloway
- Merck & Co. Inc., Kenilworth, NJ, USA.,Present address: International Discovery Service Unit, WuXi AppTec, Inc., 1690 Sumneytown Pike, Suite 150, Lansdale, PA, 19446, USA
| | - Charles A Lesburg
- Merck & Co. Inc., Kenilworth, NJ, USA.,Present address: International Discovery Service Unit, WuXi AppTec, Inc., 1690 Sumneytown Pike, Suite 150, Lansdale, PA, 19446, USA
| | - Peng Li
- WuXi AppTec, Shanghai, China
| | - Nigel Liverton
- Merck & Co. Inc., Kenilworth, NJ, USA.,Present address: International Discovery Service Unit, WuXi AppTec, Inc., 1690 Sumneytown Pike, Suite 150, Lansdale, PA, 19446, USA
| | - Peter T Meinke
- Merck & Co. Inc., Kenilworth, NJ, USA.,Present address: International Discovery Service Unit, WuXi AppTec, Inc., 1690 Sumneytown Pike, Suite 150, Lansdale, PA, 19446, USA
| | - David B Olsen
- Merck & Co. Inc., Kenilworth, NJ, USA.,Present address: International Discovery Service Unit, WuXi AppTec, Inc., 1690 Sumneytown Pike, Suite 150, Lansdale, PA, 19446, USA
| | | | | | - Ajay Ummat
- Merck & Co. Inc., Kenilworth, NJ, USA.,Present address: International Discovery Service Unit, WuXi AppTec, Inc., 1690 Sumneytown Pike, Suite 150, Lansdale, PA, 19446, USA
| | - Jie Wu
- WuXi AppTec, Shanghai, China
| | - Jin Wu
- Merck & Co. Inc., Kenilworth, NJ, USA.,Present address: International Discovery Service Unit, WuXi AppTec, Inc., 1690 Sumneytown Pike, Suite 150, Lansdale, PA, 19446, USA
| | - Nicolas Zorn
- Merck & Co. Inc., Kenilworth, NJ, USA.,Present address: International Discovery Service Unit, WuXi AppTec, Inc., 1690 Sumneytown Pike, Suite 150, Lansdale, PA, 19446, USA
| | - Steven W Ludmerer
- Merck & Co. Inc., Kenilworth, NJ, USA.,Present address: International Discovery Service Unit, WuXi AppTec, Inc., 1690 Sumneytown Pike, Suite 150, Lansdale, PA, 19446, USA
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20
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HCV Genotype 6 Increased the Risk for Hepatocellular Carcinoma Among Asian Patients With Liver Cirrhosis. Am J Gastroenterol 2017; 112:1111-1119. [PMID: 28440303 DOI: 10.1038/ajg.2017.123] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 03/14/2017] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Hepatitis C virus (HCV) infection is a well-documented risk factor for hepatocellular carcinoma (HCC). Seven HCV genotypes have been classified, and the genotypes show a great variety of geographic distribution. HCV genotype 6 is prevalent in Southeast Asia and has been less studied than the other genotypes. METHODS This follow-up study was designed to evaluate the natural history of HCV genotype 6. The cohort enrolled 851 Asian patients consisting of 222 with HCV genotype 6 and 629 with other genotypes. The incidence of HCC per 1,000 person-years of various HCV genotypes was estimated by dividing the new HCC cases to the person-years of follow-up. The adjusted hazards ratios (HRs) with 95% confidence intervals (CIs) were estimated by Cox's proportional hazards models. RESULTS After 4072 person-years of follow-up, there were 96 newly-developed HCC cases, confirming an incidence of 23.6 per 1000 person-years. By stratifying cirrhosis at study entry, the cumulative risk of HCC among HCV genotype 6 vs. non-6 was 2.9 vs. 2.2% for those without cirrhosis (P=0.45) and 76.2% (95% CI: 55.6-96.8%) vs. 36.2% (95% CI: 28.7-39.1%) for those with cirrhosis (P<0.05), respectively. Among patients with cirrhosis, HCV genotype 6 was significantly associated with HCC compared to patients with non-6 genotypes, with the adjusted HR=2.12 (1.33-3.39), P<0.05. In a model treating patients with genotypes other than 1 or 6 as the reference, the adjusted HR for HCC for HCV genotypes 1 and 6 were 1.13 (0.56-2.27) and 2.34 (1.12-4.86), respectively. CONCLUSIONS Among patients with cirrhosis, those with HCV genotype 6 infection should be given high priority for antiviral therapy to decrease HCC risk and for vigilant adherence to HCC surveillance.
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21
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Burhop A, Weck R, Atzrodt J, Derdau V. Hydrogen-Isotope Exchange (HIE) Reactions of Secondary and Tertiary Sulfonamides and Sulfonylureas with Iridium(I) Catalysts. European J Org Chem 2017. [DOI: 10.1002/ejoc.201601599] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Affiliation(s)
- Annina Burhop
- Sanofi-Aventis Deutschland GmbH; Integrated Drug Discovery; MedChem; Isotope Chemistry & Metabolite Synthesis; Industriepark Höchst Frankfurt Germany
| | - Remo Weck
- Sanofi-Aventis Deutschland GmbH; Integrated Drug Discovery; MedChem; Isotope Chemistry & Metabolite Synthesis; Industriepark Höchst Frankfurt Germany
| | - Jens Atzrodt
- Sanofi-Aventis Deutschland GmbH; Integrated Drug Discovery; MedChem; Isotope Chemistry & Metabolite Synthesis; Industriepark Höchst Frankfurt Germany
| | - Volker Derdau
- Sanofi-Aventis Deutschland GmbH; Integrated Drug Discovery; MedChem; Isotope Chemistry & Metabolite Synthesis; Industriepark Höchst Frankfurt Germany
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22
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Famiglini V, Castellano S, Silvestri R. N-Pyrrylarylsulfones with High Therapeutic Potential. Molecules 2017; 22:E434. [PMID: 28282943 PMCID: PMC6155187 DOI: 10.3390/molecules22030434] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2017] [Revised: 03/01/2017] [Accepted: 03/03/2017] [Indexed: 12/19/2022] Open
Abstract
This review illustrates the various studies made to investigate the activity of N-pyrrylarylsulfone containing compounds as potential antiviral, anticancer and SNC drugs. A number of synthetic approaches to obtain tetracyclic, tricyclic and non-cyclic compounds, and their biological activity with regard to structure-activity relationships (SARs) have been reviewed. The literature reviewed here may provide useful information on the potential of N-pyrrylarylsulfone pharmacophore as well as suggest concepts for the design and synthesis of new N-pyrrylarylsulfone based agents.
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Affiliation(s)
- Valeria Famiglini
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
| | - Sabrina Castellano
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, I-84084 Fiscano, Salerno, Italy.
| | - Romano Silvestri
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
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23
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Liang Y, de Wispelaere M, Carocci M, Liu Q, Wang J, Yang PL, Gray NS. Structure-Activity Relationship Study of QL47: A Broad-Spectrum Antiviral Agent. ACS Med Chem Lett 2017; 8:344-349. [PMID: 28337328 PMCID: PMC5346993 DOI: 10.1021/acsmedchemlett.7b00008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 02/03/2017] [Indexed: 11/30/2022] Open
Abstract
Here we report the structure-activity relationship (SAR) investigations of QL-XII-47 (QL47), a compound that possesses broad-spectrum antiviral activity against dengue virus and other RNA viruses. A medicinal chemistry campaign initiated from QL47, a previously reported covalent BTK inhibitor, to derive YKL-04-085, which is devoid of any kinase activity when screened against a panel of 468 kinases and with improved pharmacokinetic properties. Both QL47 and YKL-04-085 are potent inhibitors of viral translation and exhibit cellular antiviral activity at 35-fold lower concentrations relative to inhibition of host-cell proliferation.
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Affiliation(s)
- Yanke Liang
- Department
of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
- Departments of Biological Chemistry & Molecular
Pharmacology and Microbiology and
Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Melissanne de Wispelaere
- Departments of Biological Chemistry & Molecular
Pharmacology and Microbiology and
Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Margot Carocci
- Departments of Biological Chemistry & Molecular
Pharmacology and Microbiology and
Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Qingsong Liu
- Department
of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
- Departments of Biological Chemistry & Molecular
Pharmacology and Microbiology and
Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Jinhua Wang
- Department
of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
- Departments of Biological Chemistry & Molecular
Pharmacology and Microbiology and
Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Priscilla L. Yang
- Departments of Biological Chemistry & Molecular
Pharmacology and Microbiology and
Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Nathanael S. Gray
- Department
of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
- Departments of Biological Chemistry & Molecular
Pharmacology and Microbiology and
Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, United States
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24
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Antiviral Nucleotide Incorporation by Recombinant Human Mitochondrial RNA Polymerase Is Predictive of Increased In Vivo Mitochondrial Toxicity Risk. Antimicrob Agents Chemother 2016; 60:7077-7085. [PMID: 27645237 DOI: 10.1128/aac.01253-16] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 08/20/2016] [Indexed: 02/07/2023] Open
Abstract
Nucleoside or nucleotide inhibitors are a highly successful class of antivirals due to selectivity, potency, broad coverage, and high barrier to resistance. Nucleosides are the backbone of combination treatments for HIV, hepatitis B virus, and, since the FDA approval of sofosbuvir in 2013, also for hepatitis C virus (HCV). However, many promising nucleotide inhibitors have advanced to clinical trials only to be terminated due to unexpected toxicity. Here we describe the in vitro pharmacology of compound 1, a monophosphate prodrug of a 2'-ethynyluridine developed for the treatment of HCV. Compound 1 inhibits multiple HCV genotypes in vitro (50% effective concentration [EC50], 0.05 to 0.1 μM) with a selectivity index of >300 (50% cytotoxic concentration [CC50], 30 μM in MT-4 cells). The active triphosphate metabolite of compound 1, compound 2, does not inhibit human α, β, or γ DNA polymerases but was a substrate for incorporation by the human mitochondrial RNA polymerase (POLRMT). In dog, the oral administration of compound 1 resulted in elevated serum liver enzymes and microscopic changes in the liver. Transmission electron microscopy showed significant mitochondrial swelling and lipid accumulation in hepatocytes. Gene expression analysis revealed dose-proportional gene signature changes linked to loss of hepatic function and increased mitochondrial dysfunction. The potential of in vivo toxicity through mitochondrial polymerase incorporation by nucleoside analogs has been previously shown. This study shows that even moderate levels of nucleotide analog incorporation by POLRMT increase the risk of in vivo mitochondrial dysfunction. Based on these results, further development of compound 1 as an anti-HCV compound was terminated.
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Treatment with daclatasvir and sofosbuvir for 24 weeks without ribavirin in cirrhotic patients who failed first-generation protease inhibitors. Infection 2016; 45:103-106. [PMID: 27854063 DOI: 10.1007/s15010-016-0962-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Accepted: 11/05/2016] [Indexed: 10/20/2022]
Abstract
BACKGROUND Treatment of patients with chronic hepatitis C who failed the triple therapy with first generation of protease inhibitors is not still defined. The combined use of sofosbuvir (SOF) and daclatasvir (DCV) seems to be promising due to higher genetic barrier, good tolerance and effectiveness. METHODS We described the treatment with this drug combination in a real-life cohort of 20 cirrhotic patients with genotype 1 who failed the triple therapy. RESULTS 18 of them (90%) with Child-Pugh A, 11 (55%) with genotype 1a, 17 (85%) with more than 1 and 8 (40%) with more than 2 previous failed treatment; all patients had at baseline NS3 resistance-associated variants related to triple therapy failure. RBV was not administered due to anemia in previous treatments. The sustained virological response was 100%. CONCLUSION Treatment with SOF + DCV without RBV for 24 weeks is safe and effective in cirrhotic patients who failed triple therapy with the first generation of protease inhibitors.
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van Vlerken LG, Lieveld FI, van Meer S, Koek GH, van Nieuwkerk KMJ, Friederich P, Arends JE, Siersema PD, Burger DM, van Erpecum KJ. Adherence to ribavirin in chronic hepatitis C patients on antiviral treatment: Results from a randomized controlled trial using real-time medication monitoring. Clin Res Hepatol Gastroenterol 2016; 40:622-630. [PMID: 26867863 DOI: 10.1016/j.clinre.2015.12.014] [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] [Received: 08/05/2015] [Revised: 12/17/2015] [Accepted: 12/25/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND OBJECTIVE Adherence is essential in antiviral therapy for chronic hepatitis C. We investigated the effect of real-time medication monitoring on adherence to ribavirin. METHODS In this randomized controlled trial, patients in the intervention group received a medication dispenser that monitored ribavirin intake real-time during 24 weeks PEG-interferon/ribavirin±boceprevir or telaprevir. Patients in the control group received standard-of-care. Adherence was also measured by pill count. RESULTS Seventy-two patients were assigned to either intervention (n=35) or control groups (n=37). Median adherence by pill count was 96% (range: 43%-100%) with 30 (94%) of patients exhibiting≥80% adherence. Perfect adherence (i.e. 100%) was similar in intervention and control groups: 22 (85%) vs. 15 (75%) (P=0.47). Adherences by real-time medication monitoring and by pill count did not correlate (R=0.19, P=0.36). No predictors of poor adherence could be identified. Ribavirin trough levels after 8 weeks (median: 2.4 vs. 2.7mg/L, P=0.30) and 24 weeks (median: 3.0 vs. 3.0mg/L, P=0.69), and virological responses did not differ between intervention and control groups. CONCLUSIONS Adherence to ribavirin during PEG-interferon containing therapy in chronic hepatitis C is high. Real-time medication monitoring did not influence adherence to ribavirin, plasma ribavirin levels or virological responses.
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Affiliation(s)
- Lotte G van Vlerken
- Department of Gastroenterology and Hepatology, University Medical Center of Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands
| | - Faydra I Lieveld
- Department of Gastroenterology and Hepatology, University Medical Center of Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands; Department of Internal Medicine and Infectious Diseases, University Medical Center of Utrecht, Utrecht, The Netherlands
| | - Suzanne van Meer
- Department of Gastroenterology and Hepatology, University Medical Center of Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands
| | - Ger H Koek
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Karin M J van Nieuwkerk
- Department of Gastroenterology and Hepatology, Free University Medical Center, Amsterdam, The Netherlands
| | - Pieter Friederich
- Department of Gastroenterology and Hepatology, Catharina Hospital, Eindhoven, The Netherlands
| | - Joop E Arends
- Department of Internal Medicine and Infectious Diseases, University Medical Center of Utrecht, Utrecht, The Netherlands
| | - Peter D Siersema
- Department of Gastroenterology and Hepatology, University Medical Center of Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands; Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - David M Burger
- Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Karel J van Erpecum
- Department of Gastroenterology and Hepatology, University Medical Center of Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands.
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Kliemann DA, Tovo CV, da Veiga ABG, de Mattos AA, Wood C. Polymorphisms and resistance mutations of hepatitis C virus on sequences in the European hepatitis C virus database. World J Gastroenterol 2016; 22:8910-8917. [PMID: 27833382 PMCID: PMC5083796 DOI: 10.3748/wjg.v22.i40.8910] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2016] [Revised: 09/12/2016] [Accepted: 09/28/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the occurrence of resistant mutations in treatment-naïve hepatitis C virus (HCV) sequences deposited in the European hepatitis C virus database (euHCVdb). METHODS The sequences were downloaded from the euHCVdb (https://euhcvdb.ibcp.fr/euHCVdb/). The search was performed for full-length NS3 protease, NS5A and NS5B polymerase sequences of HCV, separated by genotypes 1a, 1b, 2a, 2b and 3a, and resulted in 798 NS3, 708 NS5A and 535 NS5B sequences from HCV genotypes 1a, 1b, 2a, 2b and 3a, after the exclusion of sequences containing errors and/or gaps or incomplete sequences, and sequences from patients previously treated with direct antiviral agents (DAA). The sequence alignment was performed with MEGA 6.06 MAC and the resulting protein sequences were then analyzed using the BioEdit 7.2.5. for mutations associated with resistance. Only positions that have been described as being associated with failure in treatment in in vivo studies, and/or as conferring a more than 2-fold change in replication in comparison to the wildtype reference strain in in vitro phenotypic assays were included in the analysis. RESULTS The Q80K variant in the NS3 gene was the most prevalent mutation, being found in 44.66% of subtype 1a and 0.25% of subtype 1b. Other frequent mutations observed in more than 2% of the NS3 sequences were: I170V (3.21%) in genotype 1a, and Y56F (15.93%), V132I (23.28%) and I170V (65.20%) in genotype 1b. For the NS5A, 2.21% of the genotype 1a sequences have the P58S mutation, 5.95% of genotype 1b sequences have the R30Q mutation, 15.79% of subtypes 2a sequences have the Q30R mutation, 23.08% of subtype 2b sequences have a L31M mutation, and in subtype 3a sequences, 23.08% have the M31L resistant variants. For the NS5B, the V321L RAV was identified in 0.60% of genotype 1a and in 0.32% of genotype 1b sequences, and the N142T variant was observed in 0.32% of subtype 1b sequences. The C316Y, S556G, D559N RAV were identified in 0.33%, 7.82% and 0.32% of genotype 1b sequences, respectively, and were not observed in other genotypes. CONCLUSION HCV mutants resistant to DAAs are found in low frequency, nevertheless they could be selected and therapy could fail due resistance substitutions in HCV genome.
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Dey D, Banerjee M. Inhibitor-Based Therapeutics for Treatment of Viral Hepatitis. J Clin Transl Hepatol 2016; 4:248-257. [PMID: 27777893 PMCID: PMC5075008 DOI: 10.14218/jcth.2016.00025] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 09/14/2016] [Accepted: 09/14/2016] [Indexed: 12/12/2022] Open
Abstract
Viral hepatitis remains a significant worldwide threat, in spite of the availability of several successful therapeutic and vaccination strategies. Complications associated with acute and chronic infections, such as liver failure, cirrhosis and hepatocellular carcinoma, are the cause of considerable morbidity and mortality. Given the significant burden on the healthcare system caused by viral hepatitis, it is essential that novel, more effective therapeutics be developed. The present review attempts to summarize the current treatments against viral hepatitis, and provides an outline for upcoming, promising new therapeutics. Development of novel therapeutics requires an understanding of the viral life cycles and viral effectors in molecular detail. As such, this review also discusses virally-encoded effectors, found to be essential for virus survival and replication in the host milieu, which may be utilized as potential candidates for development of alternative therapies in the future.
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Affiliation(s)
- Debajit Dey
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, India
| | - Manidipa Banerjee
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, India
- *Correspondence to: Dr. Manidipa Banerjee, Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Block 1A, Hauz Khas, New Delhi 110016, India. Tel: +91-11-26597538, Fax: +91-11-26597530, E-mail:
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Jonckers THM, Tahri A, Vijgen L, Berke JM, Lachau-Durand S, Stoops B, Snoeys J, Leclercq L, Tambuyzer L, Lin TI, Simmen K, Raboisson P. Discovery of 1-((2R,4aR,6R,7R,7aR)-2-Isopropoxy-2-oxidodihydro-4H,6H-spiro[furo[3,2-d][1,3,2]dioxaphosphinine-7,2'-oxetan]-6-yl)pyrimidine-2,4(1H,3H)-dione (JNJ-54257099), a 3'-5'-Cyclic Phosphate Ester Prodrug of 2'-Deoxy-2'-Spirooxetane Uridine Triphosphate Useful for HCV Inhibition. J Med Chem 2016; 59:5790-8. [PMID: 27181575 DOI: 10.1021/acs.jmedchem.6b00382] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
JNJ-54257099 (9) is a novel cyclic phosphate ester derivative that belongs to the class of 2'-deoxy-2'-spirooxetane uridine nucleotide prodrugs which are known as inhibitors of the HCV NS5B RNA-dependent RNA polymerase (RdRp). In the Huh-7 HCV genotype (GT) 1b replicon-containing cell line 9 is devoid of any anti-HCV activity, an observation attributable to inefficient prodrug metabolism which was found to be CYP3A4-dependent. In contrast, in vitro incubation of 9 in primary human hepatocytes as well as pharmacokinetic evaluation thereof in different preclinical species reveals the formation of substantial levels of 2'-deoxy-2'-spirooxetane uridine triphosphate (8), a potent inhibitor of the HCV NS5B polymerase. Overall, it was found that 9 displays a superior profile compared to its phosphoramidate prodrug analogues (e.g., 4) described previously. Of particular interest is the in vivo dose dependent reduction of HCV RNA observed in HCV infected (GT1a and GT3a) human hepatocyte chimeric mice after 7 days of oral administration of 9.
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Affiliation(s)
- Tim H M Jonckers
- Janssen Infectious Diseases - Diagnostics BVBA , Turnhoutseweg 30, 2340 Beerse, Belgium
| | - Abdellah Tahri
- Janssen Infectious Diseases - Diagnostics BVBA , Turnhoutseweg 30, 2340 Beerse, Belgium
| | - Leen Vijgen
- Janssen Infectious Diseases - Diagnostics BVBA , Turnhoutseweg 30, 2340 Beerse, Belgium
| | - Jan Martin Berke
- Janssen Infectious Diseases - Diagnostics BVBA , Turnhoutseweg 30, 2340 Beerse, Belgium
| | - Sophie Lachau-Durand
- Janssen Infectious Diseases - Diagnostics BVBA , Turnhoutseweg 30, 2340 Beerse, Belgium
| | - Bart Stoops
- Janssen Infectious Diseases - Diagnostics BVBA , Turnhoutseweg 30, 2340 Beerse, Belgium
| | - Jan Snoeys
- Janssen Infectious Diseases - Diagnostics BVBA , Turnhoutseweg 30, 2340 Beerse, Belgium
| | - Laurent Leclercq
- Janssen Infectious Diseases - Diagnostics BVBA , Turnhoutseweg 30, 2340 Beerse, Belgium
| | - Lotke Tambuyzer
- Janssen Infectious Diseases - Diagnostics BVBA , Turnhoutseweg 30, 2340 Beerse, Belgium
| | - Tse-I Lin
- Janssen Infectious Diseases - Diagnostics BVBA , Turnhoutseweg 30, 2340 Beerse, Belgium
| | - Kenny Simmen
- Janssen Infectious Diseases - Diagnostics BVBA , Turnhoutseweg 30, 2340 Beerse, Belgium
| | - Pierre Raboisson
- Janssen Infectious Diseases - Diagnostics BVBA , Turnhoutseweg 30, 2340 Beerse, Belgium
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Ahmed A, Felmlee DJ. Mechanisms of Hepatitis C Viral Resistance to Direct Acting Antivirals. Viruses 2015; 7:6716-29. [PMID: 26694454 PMCID: PMC4690891 DOI: 10.3390/v7122968] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Revised: 11/24/2015] [Accepted: 12/08/2015] [Indexed: 12/28/2022] Open
Abstract
There has been a remarkable transformation in the treatment of chronic hepatitis C in recent years with the development of direct acting antiviral agents targeting virus encoded proteins important for viral replication including NS3/4A, NS5A and NS5B. These agents have shown high sustained viral response (SVR) rates of more than 90% in phase 2 and phase 3 clinical trials; however, this is slightly lower in real-life cohorts. Hepatitis C virus resistant variants are seen in most patients who do not achieve SVR due to selection and outgrowth of resistant hepatitis C virus variants within a given host. These resistance associated mutations depend on the class of direct-acting antiviral drugs used and also vary between hepatitis C virus genotypes and subtypes. The understanding of these mutations has a clear clinical implication in terms of choice and combination of drugs used. In this review, we describe mechanism of action of currently available drugs and summarize clinically relevant resistance data.
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Affiliation(s)
- Asma Ahmed
- Plymouth University, Peninsula School of Medicine and Dentistry, Plymouth PL6 8BU, UK.
| | - Daniel J Felmlee
- Plymouth University, Peninsula School of Medicine and Dentistry, Plymouth PL6 8BU, UK.
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Gutierrez JA, Lawitz EJ, Poordad F. Interferon-free, direct-acting antiviral therapy for chronic hepatitis C. J Viral Hepat 2015; 22:861-70. [PMID: 26083155 DOI: 10.1111/jvh.12422] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Accepted: 03/11/2015] [Indexed: 12/13/2022]
Abstract
The treatment environment for chronic hepatitis C has undergone a revolution, particularly in genotype 1. Gone are interferon-based therapy and its associated tolerability challenges, inadequate response rates and numerous baseline factors that affect response to therapy. New and emerging treatment regimens employ all-oral combinations of direct-acting antiviral agents, and results of clinical trials suggest that these regimens routinely achieve cure rates >90%, even in patients who failed prior interferon-based triple therapy. In 2015, three all-oral FDA-approved regiments will be available for genotype 1 (sofosbuvir /ledipasvir, sofosbuvir/simeprevir, and paritaprevir/r/ombitasvir/dasabuvir). Furthermore, new treatment combinations appear to be more tolerable and require shorter duration of therapy. We provide an overview of the classes of direct-acting antiviral agents (DAAs), the clinical factors affecting their integration into combination therapies and recent findings from trials of such combination therapies in patients with genotype 1 HCV infection.
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Affiliation(s)
- J A Gutierrez
- The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA
| | - E J Lawitz
- The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA
| | - F Poordad
- The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA
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Lontok E, Harrington P, Howe A, Kieffer T, Lennerstrand J, Lenz O, McPhee F, Mo H, Parkin N, Pilot-Matias T, Miller V. Hepatitis C virus drug resistance-associated substitutions: State of the art summary. Hepatology 2015; 62:1623-32. [PMID: 26095927 DOI: 10.1002/hep.27934] [Citation(s) in RCA: 239] [Impact Index Per Article: 23.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 06/06/2015] [Indexed: 12/12/2022]
Abstract
UNLABELLED Hepatitis C virus (HCV) drug development has resulted in treatment regimens composed of interferon-free, all-oral combinations of direct-acting antivirals. While the new regimens are potent and highly efficacious, the full clinical impact of HCV drug resistance, its implications for retreatment, and the potential role of baseline resistance testing remain critical research and clinical questions. In this report, we discuss the viral proteins targeted by HCV direct-acting antivirals and summarize clinically relevant resistance data for compounds that have been approved or are currently in phase 3 clinical trials. CONCLUSION This report provides a comprehensive, systematic review of all resistance information available from sponsors' trials as a tool to inform the HCV drug development field.
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Affiliation(s)
- Erik Lontok
- Forum for Collaborative HIV Research, University of California at Berkeley, Washington, DC
| | - Patrick Harrington
- Center for Drug Evaluation and Research, Office of Antimicrobial Products, Division of Antiviral Products, US Food and Drug Administration, Silver Spring, MD
| | - Anita Howe
- Merck Research Laboratories, West Point, PA
| | | | | | - Oliver Lenz
- Janssen Infectious Diseases, Beerse, Belgium
| | - Fiona McPhee
- Bristol-Myers Squibb Research and Development, Wallingford, CT
| | | | | | | | - Veronica Miller
- Forum for Collaborative HIV Research, University of California at Berkeley, Washington, DC
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HCV Drug Resistance Challenges in Japan: The Role of Pre-Existing Variants and Emerging Resistant Strains in Direct Acting Antiviral Therapy. Viruses 2015; 7:5328-42. [PMID: 26473914 PMCID: PMC4632384 DOI: 10.3390/v7102876] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 09/24/2015] [Accepted: 09/28/2015] [Indexed: 12/21/2022] Open
Abstract
Sustained virological response (SVR) rates have increased dramatically following the approval of direct acting antiviral (DAA) therapies. While individual DAAs have a low barrier to resistance, most patients can be successfully treated using DAA combination therapy. However, DAAs are vulnerable to drug resistance, and resistance-associated variants (RAVs) may occur naturally prior to DAA therapy or may emerge following drug exposure. While most RAVs are quickly lost in the absence of DAAs, compensatory mutations may reinforce fitness. However, the presence of RAVs does not necessarily preclude successful treatment. Although developments in hepatitis C virus (HCV) therapy in Asia have largely paralleled those in the United States, Japan’s July 2014 approval of asunaprevir plus daclatasvir combination therapy as the first all-oral interferon-free therapy was not repeated in the United States. Instead, two different combination therapies were approved: sofosbuvir/ledipasvir and paritaprevir/ritonavir/ombitasvir/dasabuvir. This divergence in treatment approaches may lead to differences in resistance challenges faced by Japan and the US. However, the recent approval of sofosbuvir plus ledipasvir in Japan and the recent submissions of petitions for approval of paritaprevir/ritonavir plus ombitasvir suggest a trend towards a new consensus on emerging DAA regimens.
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Design, synthesis and antiviral evaluation of 2'-C-methyl branched guanosine pronucleotides: the discovery of IDX184, a potent liver-targeted HCV polymerase inhibitor. Future Med Chem 2015; 7:1675-700. [PMID: 26424162 DOI: 10.4155/fmc.15.96] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Ribonucleoside analogs possessing a β-methyl substituent at the 2'-position of the d-ribose moiety have been previously discovered to be potent and selective inhibitors of hepatitis C virus (HCV) replication, their triphosphates acting as alternative substrate inhibitors of the HCV RdRp NS5B. Results/methodology: In this article, the authors detail the synthesis, anti-HCV evaluation in cell-based replicon assays and structure-activity relationships of several phosphoramidate diester derivatives of 2'-C-methylguanosine (2'-MeG). CONCLUSION The most promising compound, namely the O-[S-(hydroxyl)pivaloyl-2-thioethyl]{abbreviated as O-[(HO)tBuSATE)]} N-benzylamine phosphoramidate diester derivative (IDX184), was selected for further in vivo studies, and was the first clinical pronucleotide evaluated for the treatment of chronic hepatitis C up to Phase II trials.
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NMR-based conformational analysis of 2′,6-disubstituted uridines and antiviral evaluation of new phosphoramidate prodrugs. Bioorg Med Chem 2015. [DOI: 10.1016/j.bmc.2015.07.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Latli B, Hrapchak M, Chevliakov M, Li G, Campbell S, Busacca CA, Senanayake CH. Synthesis of deleobuvir, a potent hepatitis C virus polymerase inhibitor, and its major metabolites labeled with carbon-13 and carbon-14. J Labelled Comp Radiopharm 2015; 58:250-60. [PMID: 25964148 DOI: 10.1002/jlcr.3294] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 03/10/2015] [Accepted: 04/01/2015] [Indexed: 01/09/2023]
Abstract
Deleobuvir, (2E)-3-(2-{1-[2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxamido]cyclobutyl}-1-methyl-1H-benzimidazol-6-yl)prop-2-enoic acid (1), is a non-nucleoside, potent, and selective inhibitor of hepatitis C virus NS5B polymerase. Herein, we describe the detailed synthesis of this compound labeled with carbon-13 and carbon-14. The synthesis of its three major metabolites, namely, the reduced double bond metabolite (2) and the acyl glucuronide derivatives of (1) and (2), is also reported. Aniline-(13) C6 was the starting material to prepare butyl (E)-3-(3-methylamino-4-nitrophenyl-(13) C6 )acrylate [(13) C6 ]-(11) in six steps. This intermediate was then used to obtain [(13) C6 ]-(1) and [(13) C6 ]-(2) in five and four more steps, respectively. For the radioactive synthesis, potassium cyanide-(14) C was used to prepare 1-cylobutylaminoacid [(14) C]-(23) via Buchrer-Bergs reaction. The carbonyl chloride of this acid was then used to access both [(14) C]-(1) and [(14) C]-(2) in four steps. The acyl glucuronide derivatives [(13) C6 ]-(3), [(13) C6 ]-(4) and [(14) C]-(3) were synthesized in three steps from the acids [(13) C6 ]-(1), [(13) C6 ]-(2) and [(14) C]-(1) using known procedures.
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Affiliation(s)
- Bachir Latli
- Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT, 06877-0368, USA
| | - Matt Hrapchak
- Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT, 06877-0368, USA
| | - Maxim Chevliakov
- Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT, 06877-0368, USA
| | - Guisheng Li
- Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT, 06877-0368, USA
| | - Scot Campbell
- Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT, 06877-0368, USA
| | - Carl A Busacca
- Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT, 06877-0368, USA
| | - Chris H Senanayake
- Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT, 06877-0368, USA
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McQuaid T, Savini C, Seyedkazemi S. Sofosbuvir, a Significant Paradigm Change in HCV Treatment. J Clin Transl Hepatol 2015; 3:27-35. [PMID: 26357632 PMCID: PMC4542085 DOI: 10.14218/jcth.2014.00041] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2014] [Revised: 01/18/2015] [Accepted: 01/19/2015] [Indexed: 12/11/2022] Open
Abstract
Nucleotide compounds like sofosbuvir, acyclovir, and tenofovir have proven to be amongst the most potent orally available antiviral treatments. These drugs exhibit high efficacy and a wide therapeutic index, with demonstrated utility in a number of chronic viral infections. The approval of Sovaldi™, brand name for sofosbuvir, by the U.S. Food and Drug Administration heralded improvements in chronic hepatitis C virus (HCV) treatment. Sofosbuvir was originally discovered by Pharmasset Corporation and named PSI-7977. It was subsequently acquired and advanced through phase 3 development by Gilead Sciences, Inc. In Sofosbuvir both a unique pharmacology and a high specificity for the HCV ribonucleic acid polymerase are present in a molecule that is well tolerated and highly efficacious. Phase 2 and 3 clinical trials have consistently demonstrated durable and high rates of sustained virologic response (SVR), curing patients in excess of 80% in all genotypes and >90% in treatment-naïve subjects being administered combination therapy with other agents. Harvoni(®) is the combination of sofosbuvir and the NS5A inhibitor ledipasvir in a fixed-dose oral tablet, and it has demonstrated high SVR rates in patients infected with HCV genotype 1, without the need for exogenous interferon and/or ribavirin. Here, we discuss the discovery, development, pharmacologic characterization, and results from the phase 3 trials of sofosbuvir. Hepatitis C is a chronic disease, for which most patients have been undiagnosed, are unwilling to start treatment, or are ineligible for treatment because of the high toxicity and low efficacy of interferon and ribavirin-based therapy. Clinical studies with sofosbuvir have demonstrated significant improvement over the prior standard of care, thus ushering in a new paradigm of HCV treatment and an update of treatment guidelines.
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Affiliation(s)
- Thomas McQuaid
- Correspondence to: Thomas McQuaid, Gilead Sciences, 25 Marshall Street Unit 2C, Norwalk, CT 06854, USA. Tel: +1-917-566-3554, Fax: +1-203-274-6713. E-mail:
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Chayama K, Mitsui F, Hayes CN. Optimizing triple therapy and IFN/RBV-free regimens for hepatitis C virus infection. Expert Rev Gastroenterol Hepatol 2015; 9:21-30. [PMID: 25220206 DOI: 10.1586/17474124.2015.960394] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Treatment of chronic hepatitis C virus infection has substantially improved following the advent of direct acting antiviral (DAA) agents. Although the first generation protease inhibitors telaprevir and boceprevir improved sustained viral response (SVR) rates, adverse events remain severe and immature termination of the therapy is frequent; however, intensive dose modification has improved completion and SVR rates. Interferon-free DAA combination therapies, such as asunaprevir and daclatasvir dual therapy are under development and promise higher SVR rates with fewer adverse events. Resistance monitoring and modification of DAA therapy based on pre-existing or de novo resistance variants should be considered. Future therapies are expected to have pan-genotypic activity with shorter duration and improved tolerability, even among cirrhotic and liver transplant patients.
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Affiliation(s)
- Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
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Hayes CN, Chayama K. Emerging treatments for chronic hepatitis C. J Formos Med Assoc 2014; 114:204-15. [PMID: 25300586 DOI: 10.1016/j.jfma.2014.09.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2014] [Revised: 08/21/2014] [Accepted: 09/01/2014] [Indexed: 02/06/2023] Open
Abstract
Advances in understanding the hepatitis C virus (HCV) life cycle and the urgent need to find complementary direct-acting antiviral (DAA) therapies has led to substantial advancements in treating chronic hepatitis C. The introduction of telaprevir and boceprevir in 2011 increased the sustained virological response (SVR) rate from approximately 50% to > 70%, but this therapy further restricted patient eligibility and is only approved for treating HCV genotype 1 infection. Interferon has long remained the backbone of HCV therapy and helps prevent viral breakthrough. However, interferon has limited effectiveness and is associated with severe adverse effects and toxicity, especially among cirrhotic patients. Moving to interferon-free therapies should greatly improve SVR rates and offer new treatments for other HCV genotypes and for ineligible patients or patients failing to respond to prior therapies. However, without the relative safety of interferon to suppress viral escape, vigilance will be required to select appropriate therapies and monitor resistance. Several DAAs are currently undergoing clinical trials and will soon undergo the approval process. Goals of future HCV clinical research will be to identify combinations of DAAs with high genetic barriers, investigate optimal treatment doses and durations, and determine the role of ribavirin in DAA therapies.
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Affiliation(s)
- C Nelson Hayes
- Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan.
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Efficacy and safety of pegylated interferon plus ribavirin therapy for chronic hepatitis C genotype 6: a meta-analysis. PLoS One 2014; 9:e100128. [PMID: 24963667 PMCID: PMC4070902 DOI: 10.1371/journal.pone.0100128] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Accepted: 05/21/2014] [Indexed: 02/07/2023] Open
Abstract
Background Hepatitis C genotype 6 (HCV-6) is prevalent in Southeast Asia. Data on the efficacy of direct-acting antiviral agents in chronic HCV-6 patients is limited and pegylated interferon (Peg-IFN) plus ribavirin (RBV) combination therapy remains standard therapy for those patients. Aim Meta-analysis was performed to assess the efficacy and safety of Peg-IFN plus RBV combination therapy for chronic HCV-6 patients. Methods Relevant studies were found by database search through Medline, Embase, Web of Science and The Cochrane Library. All published clinical trials assessing the efficacy of Peg-IFN plus RBV combination therapy for chronic HCV-6 patients were included. Sustained virological response rate (SVR) was pooled. We performed additional meta-analyses to compare the SVR outcomes of 24 versus 48 weeks of treatment in four head-to-head trials. Another second meta-analysis was also conducted to compare the efficacy of combination Peg-IFN plus RBV therapy in HCV-6 versus HCV-1 patients. Results Thirteen studies met the inclusion criteria. The pooled SVR of all single arms was 75% (95% CI: 0.68–0.81). The SVR of 24 weeks treatment was significantly lower than that at 48 weeks, with a risk difference of −14% (95% CI: −0.25 to −0.02, p = 0.02). However, when restricted to the patients with rapid virological response (RVR), there was no significant effect on SVR between these two treatment groups, with a risk difference of −1% (95% CI: −0.1 to 0.07, p = 0.67). The SVR in HCV-6 patients was significantly higher than that in HCV-1 patients, with a relative risk of 1.35 (95% CI: 1.16–1.57, p<0.001). Side effects were common, but rarely caused treatment discontinuation. Conclusions The results of this meta-analysis suggest that Peg-IFN plus RBV is effective and safe for HCV-6 patients. Shortening treatment seems to be feasible in HCV-6 patients with RVR when tolerance to treatment is poor. However, this decision should be made cautiously.
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Poveda E, Wyles DL, Mena A, Pedreira JD, Castro-Iglesias A, Cachay E. Update on hepatitis C virus resistance to direct-acting antiviral agents. Antiviral Res 2014; 108:181-91. [PMID: 24911972 DOI: 10.1016/j.antiviral.2014.05.015] [Citation(s) in RCA: 152] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Revised: 05/13/2014] [Accepted: 05/22/2014] [Indexed: 12/12/2022]
Abstract
Resistance to direct-acting antiviral (DAA) agents against hepatitis C virus (HCV) infection is driven by the selection of mutations at different positions in the NS3 protease, NS5B polymerase and NS5A proteins. With the exception of NS5B nucleos(t)ide inhibitors, most DAAs possess a low genetic barrier to resistance, with significant cross-resistance between compounds belonging to the same family. However, a specific mutation profile is associated with each agent or drug class and varies depending on the genotype/subtype (e.g., genotype 1b showed higher rates of sustained virological response (SVR) and a higher genetic barrier for resistance than genotype 1a). Moreover, some resistance mutations exist as natural polymorphisms in certain genotypes/subtypes at frequencies that require baseline drug resistance testing before recommending certain antivirals. For example, the polymorphism Q80K is frequently found among genotype 1a (19-48%) and is associated with resistance to simeprevir. Similarly, L31M and Y93H, key resistance mutations to NS5A inhibitors, are frequently found (6-12%) among NS5A genotype 1 sequences. In particular, the presence of these polymorphisms may be of relevance in poorly interferon-responsive patients (i.e., null responders and non-CC IL28B) under DAA-based therapies in combination with pegylated interferon-α plus ribavirin. The relevance of pre-existing resistance mutations for responses to interferon-free DAA therapies is unclear for most regimens and requires further study.
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Affiliation(s)
- Eva Poveda
- Grupo de Virología Clínica, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Spain.
| | - David L Wyles
- Department of Medicine, Owen Clinic and Division of Infectious Diseases, UC San Diego, USA
| | - Alvaro Mena
- Grupo de Virología Clínica, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Spain
| | - José D Pedreira
- Grupo de Virología Clínica, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Spain
| | - Angeles Castro-Iglesias
- Grupo de Virología Clínica, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Spain
| | - Edward Cachay
- Department of Medicine, Owen Clinic and Division of Infectious Diseases, UC San Diego, USA
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Manfroni G, Cannalire R, Barreca ML, Kaushik-Basu N, Leyssen P, Winquist J, Iraci N, Manvar D, Paeshuyse J, Guhamazumder R, Basu A, Sabatini S, Tabarrini O, Danielson UH, Neyts J, Cecchetti V. The versatile nature of the 6-aminoquinolone scaffold: identification of submicromolar hepatitis C virus NS5B inhibitors. J Med Chem 2013; 57:1952-63. [PMID: 24131104 DOI: 10.1021/jm401362f] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
We have previously reported that the 6-aminoquinolone chemotype is a privileged scaffold to obtain antibacterial and antiviral agents. Herein we describe the design, synthesis, and enzymatic and cellular characterization of new 6-aminoquinolone derivatives as potent inhibitors of NS5B polymerase, an attractive and viable therapeutic target to develop safe anti-HCV agents. The 6-amino-7-[4-(2-pyridinyl)-1-piperazinyl]quinolone derivative 8 proved to be the best compound of this series, exhibiting an IC50 value of 0.069 μM against NS5B polymerase and selective antiviral effect (EC50 = 3.03 μM) coupled with the absence of any cytostatic effect (CC50 > 163 μM; SI > 54) in Huh 9-13 cells carrying a HCV genotype 1b, as measured by MTS assay. These results indicate that the 6-aminoquinolone scaffold is worthy of further investigation in the context of NS5B-targeted HCV drug discovery programs.
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Affiliation(s)
- Giuseppe Manfroni
- Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia , Via del Liceo 1, 06123 Perugia, Italy
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Bunchorntavakul C, Chavalitdhamrong D, Tanwandee T. Hepatitis C genotype 6: A concise review and response-guided therapy proposal. World J Hepatol 2013; 5:496-504. [PMID: 24073301 PMCID: PMC3782687 DOI: 10.4254/wjh.v5.i9.496] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Revised: 08/05/2013] [Accepted: 08/13/2013] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C genotype 6 is endemic in Southeast Asia [prevalence varies between 10%-60% among all hepatitis C virus (HCV) infection], as well as also sporadically reported outside the area among immigrations. The diagnosis of HCV genotype can be inaccurate with earlier methods of genotyping due to identical 5’-UTR between genotype 6 and 1b, hence the newer genotyping methods with core sequencing are preferred. Risk factors and clinical course of HCV genotype 6 do not differ considerably from other genotypes. Treatment outcome of HCV genotype 6 with a combination of pegylated interferon and ribavirin is superior to genotype 1, and nearly comparable to genotype 3, with expected sustained virological response (SVR) rates of 60%-90%. Emerging data suggests that a shorter course 24-wk treatment is equally effective as a standard 48-wk treatment, particularly for those patients who attained undetectable HCV RNA at week 4 (RVR). In addition, baseline and on-treatment predictors of response used for other HCV genotypes appear effective with genotype 6. Although some pan-genotypic direct-acting antivirals have completed phase II/III studies (sofosbuvir and simeprevir) with clinical benefit demonstrated in small number of patients with genotype 6, broad availability of these agents in Southeast Asia may not be expected in the near future. While awaiting the newer therapy, response-guided therapy seems appropriate for patients with HCV genotype 6. Patients with RVR (representing > 70% of patients) are suitable for 24-wk treatment with expected SVR rates > 80%. Patients without RVR and/or those with poor response predictors may benefit from 48 wk of therapy, and a detectable HCV RNA at week 12 (with no early virological response) serves as a stopping rule. This treatment scheme is likely to have a major economic impact on HCV therapy, particularly in Southeast Asia, wherein treatment can be truncated securely in the majority of patients with HCV genotype 6.
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Conteduca V, Sansonno D, Russi S, Pavone F, Dammacco F. Therapy of chronic hepatitis C virus infection in the era of direct-acting and host-targeting antiviral agents. J Infect 2013; 68:1-20. [PMID: 24012819 DOI: 10.1016/j.jinf.2013.08.019] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Revised: 08/07/2013] [Accepted: 08/22/2013] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Chronic hepatitis C virus (HCV) infection represents a leading worldwide medical and social problem. The expanding knowledge of HCV lifecycle has led to the development of novel antiviral agents that: a) specifically target a viral function (direct-acting antivirals), or b) specifically inhibit viral replication. The present review describes the novel anti-HCV drugs that have been better studied at the time of this writing and the current two types of treatment, namely interferon-based and interferon-free regimens. In addition, predictive factors, virological responses, side-effects, and resistance mechanisms of the novel agents are summarized. CONCLUSIONS The introduction of novel antiviral agents is remarkably changing the therapeutic combinations aimed at improving virological responses both for easy-to-cure and difficult-to-treat patients. Since additional, effective drugs are under advanced development, it seems reasonable to expect that further therapeutic and prognostic improvements will be achieved in the near future.
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Affiliation(s)
- Vincenza Conteduca
- Section of Internal Medicine and Clinical Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
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