The 2014 Short Guide to Hepatitis C
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Antiviral Chemistry & Chemotherapy's Current Antiviral Agents Factfile 2006
RNA_title_sheet 22/8/06 10:13 Page 1 Antiviral Chemistry & Chemotherapy’s current antiviral agents FactFile 2006 (1st edition) The RNA viruses RNA_title_sheet 22/8/06 10:13 Page 2 RNA 22/8/06 09:31 Page 129 Antiviral Chemistry & Chemotherapy 17.3 FactFiille:: RNA viiruses Symmetrel, Mantadix Amantadine Adamantan-1-amine hydrochloride, l-adamantanamine, aman- tadine hydrochloride. Novartis References: 1,64,65 Principal target virus: Influenza A virus. Other activities: HCV. H Mode of action: M2 ion channel inhibitor. Clinical stage: Licensed. Adamantine (cyclic primary amine) derivative used for the treatment and prophylaxis of influenza A virus infections. Rapid emergence of resistence has limited it use. Sometimes used to treat HCV infection in combination with interferon and ribavirin. NH2.HCI H H Ciluprevir (1S,4R,6S,14S,18R)-7Z-14-Cyclopentyloxycarbonylamino-18-[2-(2- isopropylamino-thiazol-4-yl)-7-methoxy-quinolin-4-yloxy]-2,15 Boehringer Ingelheim (Canada) Ltd. R&D dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid, BILN 2061. References: 66,67,68,69 OMe Principal target virus: HCV Mode of action: PI Development of ciluprevir has been discontinued. Ciluprevir is a novel small molecule anti-hepatitis C compound. It is N the first in a new class of investigational antiviral drugs, HCV PIs. N H O N CH S 3 O H C H 3 O N N OH O O N O H Tamiflu Oseltamivir Ethyl ester of (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethyl- propoxy)-1-cyclohexane-1-carboxylic acid, GS4104, Ro-64-0796. -
Novel HCV Inhibitors
The UseNovel of Antivirals HCV toInhibitors Rapidly Contain Outbreaks of the Classical Swine Fever Virus Johan Neyts Rega Institute, KULeuven, Leuven Belgium Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Selective Inhibitors of HCV Replication that Target NS Proteins Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus The NS2 cysteine protease NS2/3 cleavage is essential for replication and assembly N N C C Active Site 1 Active Site 2 Lorenz et al. Nature (2006) 442: 831-5 Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus The HCV NS3 serine protease N-terminal domain : a serine protease in the presence of the NS4A cofactor protein C-terminal domain : RNA helicase De Francesco et al. 2001 Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus NS3 protease product based inhibitors carboxy-terminal hexapeptide products as an active-site affinity anchor BILN-2061 Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Proof of concept with BILN-2061 (Ciluprevir) Lamarre et al., Nature. (2003) 426:186-9. Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Telaprevir monotherapy placebo 1250 mg q12h 450 mg q8h 750 mg q8h Reesink et al., Hepatology (2005) 42 : 234A Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus The Major VX-950 and BILN2061 Resistance Mutations Do Not Cause Cross-resistance ITMN-191 Ciluprevir Lin, C. -
Interferon-Based and Interferon-Free New Treatment Options
Interferon-based and interferon-free new treatment options White Nights of Hepatology St. Petersburg, 7. June 2013 Christoph Sarrazin Klinikum der J. W. Goethe-Universität Medizinische Klinik I Frankfurt am Main Mode of action of Interferons natural immunomodulatory effects IFN-stimulated gene activation Antiviral Apoptotic Immunomodulatory activity activity activity B-cell proliferation Reduced transcription Elevates apoptosis by CTL proliferation Reduced translation multiple mechanisms MHC upregulation Reduced RNA stability Augments NK activity Host-mediated effects are important for DAA combination therapy • Potency and additive effects • Prevention of resistance and viral breakthrough Different types of Interferons Type I Interferons Type III Interferons Broad receptor Receptors distribution distributed throughout various primarily in body tissues epithelial cells and hepatocytes Antiviral effects Antiviral effects Adverse events of Type I IFNs treatment Peg‐Intron • Flu-like symptoms PegIFN‐2a Type III IFNs Potentially fewer • Haematologic IFN omega Peg‐IFN‐ adverse events disorders IFN‐alfa‐2b XL lambda than with type I • Psychiatric Belerofon (Peg‐rIL‐29) interferons symptoms Albuferon Locteron Adapted from 1. Marcello T et al. Gastroenterology 2006;131:1887–98; 2. Muir AJ et al. 2009 AASLD. Abstract 1591; 3. O'Brien TR. Nat Genet. 2009;41:1048–50. PEG-Interferon alfa / Ribavirin Approval studies: efficacy Approval study (n=1530) Approval study (n=1121) Therapy: IFN vs. PEG-IFN alfa 2b Therapy: IFN vs. PEG-IFN alfa 2a 1,0/1,5µg/kgKG -
Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 197 Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors Targeting Different Genotypes and Drug-Resistant Variants ANNA KARIN BELFRAGE ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6192 ISBN 978-91-554-9166-6 UPPSALA urn:nbn:se:uu:diva-243317 2015 Dissertation presented at Uppsala University to be publicly examined in B41 BMC, Husargatan 3, Uppsala, Friday, 27 March 2015 at 09:15 for the degree of Doctor of Philosophy (Faculty of Pharmacy). The examination will be conducted in Swedish. Faculty examiner: Ulf Ellervik (Lunds tekniska högskola). Abstract Belfrage, A. K. 2015. Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors. Targeting Different Genotypes and Drug-Resistant Variants. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 197. 108 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-554-9166-6. Since the first approved hepatitis C virus (HCV) NS3 protease inhibitors in 2011, numerous direct acting antivirals (DAAs) have reached late stages of clinical trials. Today, several combination therapies, based on different DAAs, with or without the need of pegylated interferon-α injection, are available for chronic HCV infections. The chemical foundation of the approved and late-stage HCV NS3 protease inhibitors is markedly similar. This could partly explain the cross-resistance that have emerged under the pressure of NS3 protease inhibitors. The first-generation NS3 protease inhibitors were developed to efficiently inhibit genotype 1 of the virus and were less potent against other genotypes. The main focus in this thesis was to design and synthesize a new class of 2(1H)-pyrazinone based HCV NS3 protease inhibitors, structurally dissimilar to the inhibitors evaluated in clinical trials or approved, potentially with a unique resistance profile and with a broad genotypic coverage. -
Development of Novel Antiviral Therapies for Hepatitis C Virus Kai Lin** (Novartis Institutes for Biomedical Research, Inc
VIROLOGICA SINICA, August 2010, 25 (4):246-266 DOI 10.1007/s12250-010-3140-2 © Wuhan Institute of Virology, CAS and Springer-Verlag Berlin Heidelberg 2010 Development of Novel Antiviral Therapies for Hepatitis C Virus Kai Lin** (Novartis Institutes for BioMedical Research, Inc. Cambridge, Massachusetts 02139, USA) Abstract: Over 170 million people worldwide are infected with hepatitis C virus (HCV), a major cause of liver diseases. Current interferon-based therapy is of limited efficacy and has significant side effects and more effective and better tolerated therapies are urgently needed. HCV is a positive, single-stranded RNA virus with a 9.6 kb genome that encodes ten viral proteins. Among them, the NS3 protease and the NS5B polymerase are essential for viral replication and have been the main focus of drug discovery efforts. Aided by structure-based drug design, potent and specific inhibitors of NS3 and NS5B have been identified, some of which are in late stage clinical trials and may significantly improve current HCV treatment. Inhibitors of other viral targets such as NS5A are also being pursued. However, HCV is an RNA virus characterized by high replication and mutation rates and consequently, resistance emerges quickly in patients treated with specific antivirals as monotherapy. A complementary approach is to target host factors such as cyclophilins that are also essential for viral replication and may present a higher genetic barrier to resistance. Combinations of these inhibitors of different mechanism are likely to become the essential components of future HCV therapies in order to maximize antiviral efficacy and prevent the emergence of resistance. -
Reviews in Basic and Clinical Gastroenterology
GASTROENTEROLOGY 2010;138:447–462 REVIEWS IN BASIC AND CLINICAL GASTROENTEROLOGY REVIEWS IN BASIC AND CLINICAL John P. Lynch and David C. Metz, Section Editors GASTROENTEROLOGY Resistance to Direct Antiviral Agents in Patients With Hepatitis C Virus Infection CHRISTOPH SARRAZIN and STEFAN ZEUZEM J. W. Goethe-University Hospital, Medizinische Klinik 1, Frankfurt am Main, Germany Chronic hepatitis C virus (HCV) infection is one of agents that are also named specific, targeted antiviral the major causes of cirrhosis, hepatocellular carci- therapies (STAT-C) for HCV infection are in phase 1–3 noma, and liver failure that leads to transplantation. trials. We review resistance to DAA agents, focusing on The current standard treatment, a combination of compounds in development such as reagents that target pegylated interferon alfa and ribavirin, eradicates the the HCV nonstructural (NS)3 protease, the NS5A pro- virus in only about 50% of patients. Directly acting tein, and the RNA-dependent RNA polymerase NS5B. We antiviral (DAA) agents, which inhibit HCV replica- also discuss indirect inhibitors or compounds that in- tion, are in phase 1, 2, and 3 trials; these include hibit HCV replication by not yet completely resolved reagents that target the nonstructural (NS)3 protease, mechanisms, such as cyclophilin inhibitors, nitazox- the NS5A protein, the RNA-dependent RNA-polymer- anide, and silibinin (Table 1, Figure 1). ase NS5B, as well as compounds that directly inhibit HCV replication through interaction with host cell Parameters That Affect Resistance proteins. Because of the high genetic heterogeneity of Heterogeneity of HCV HCV and its rapid replication, monotherapy with HCV has a high rate of turnover; its half-life was DAA agents poses a high risk for selection of resistant estimated to be only 2–5 hours, with the production and variants. -
WO 2012/158271 Al 22 November 2012 (22.11.2012) P O P C T
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2012/158271 Al 22 November 2012 (22.11.2012) P O P C T (51) International Patent Classification: (74) Agent: PINO, Mark, J.; Connolly Bove Lodge & Hutz C07D 417/04 (2006.01) A61K 31/542 (2006.01) LLP, 1875 Eye Street, Nw, Suite 1100, Washington, DC C07D 513/04 (2006.01) A61P 31/14 (2006.01) 20006 (US). A61K 31/5415 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/US20 12/032297 AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (22) International Filing Date: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, 5 April 2012 (05.04.2012) HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, (25) Filing Language: English KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (26) Publication Language: English OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, (30) Priority Data: SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, 61/472,286 6 April 201 1 (06.04.201 1) US TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant (for all designated States except US) : ANADYS (84) Designated States (unless otherwise indicated, for every PHARMACEUTICALS, INC. -
Unravelling the Evolutionary Relationships of Hepaciviruses Within and Across Rodent Hosts
bioRxiv preprint doi: https://doi.org/10.1101/2020.10.09.332932; this version posted October 9, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Unravelling the evolutionary relationships of hepaciviruses within and across rodent hosts Magda Bletsa1, Bram Vrancken1, Sophie Gryseels1;2, Ine Boonen1, Antonios Fikatas1, Yiqiao Li1, Anne Laudisoit3, Sebastian Lequime1, Josef Bryja4, Rhodes Makundi5, Yonas Meheretu6, Benjamin Dudu Akaibe7, Sylvestre Gambalemoke Mbalitini7, Frederik Van de Perre8, Natalie Van Houtte8, Jana Teˇsˇ´ıkova´ 4;9, Elke Wollants1, Marc Van Ranst1, Jan Felix Drexler10;11, Erik Verheyen8;12, Herwig Leirs8, Joelle Gouy de Bellocq4 and Philippe Lemey1∗ 1Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven – University of Leuven, Leuven, Belgium 2Department of Ecology and Evolutionary Biology, University of Arizona, Tucson, USA 3EcoHealth Alliance, New York, USA 4Institute of Vertebrate Biology of the Czech Academy of Sciences, Brno, Czech Republic 5Pest Management Center – Sokoine University of Agriculture, Morogoro, Tanzania 6Department of Biology and Institute of Mountain Research & Development, Mekelle University, Mekelle, Ethiopia 7Department of Ecology and Animal Resource Management, Faculty of Science, Biodiversity Monitoring Center, University of Kisangani, Kisangani, Democratic Republic -
HCV Eradication with Direct Acting Antivirals (Daas)?
HCV eradication with direct acting antivirals (DAAs)? Emilie Estrabaud Service d’Hépatologie et INSERM UMR1149, AP-HP Hôpital Beaujon, Paris, France. [email protected] HCV eradication with direct acting antivirals (DAAs)? HCV replication HCV genome and DAAs targets NS3 inhibitors NS5A inhibitors NS5B inhibitors Take home messages HCV viral cycle Asselah et al. Liver Int. 2015;35 S1:56-64. Direct acting antivirals 5’NTR Structural proteins Nonstructural proteins 3’NTR Metalloprotease Envelope Serine protease Glycoproteins RNA Capsid RNA helicase Cofactors Polymerase C E1 E2 NS1 NS2 NS3 NS4A NS4B NS5A NS5B Protease Inhibitors NS5A Inhibitors Polymerase Inhibitors Telaprevir Daclatasvir Nucs Non-Nucs Boceprevir Ledipasvir Simeprevir ABT-267 Sofosbuvir ABT-333 Faldaprevir GS-5816 VX-135 Deleobuvir Asunaprevir Direct Acting Antivirals: 2015 Asselah et al. Liver Int. 2015;35 S1:56-64. Genetic barrier for HCV direct acting antivirals High Nucleos(t)ide 1 mutation= high cost to Analog Inhibitors fitness, 2-3 additional mutations to increase fitness 2 st generation Protease Inhibitors n Non Nucleos(t)ide Analog Inhibitors : NS5 A Inhibitors 1 st generation Protease Inhibitors 1 mutation= low cost to fitness Low Halfon et al. J Hepatol 2011. Vol 55(1):192-206. HCV protease inhibitors (PI) Inhibit NS3/NS4A serine protease responsible for the processing of the polyprotein 1st generation 1st generation, 2nd wave 2nd generation Resistance low low high barrier Genotype activity 1: 1 a< 1b All except 3 all Drug drug Important Less Less interaction Drugs Boceprevir Simeprevir (Janssen) MK-5172 Telaprevir Faldaprevir (BI) ACH-2684 Paritaprevir (ABT-450)/r (AbbVie) Vedroprevir (Gilead) Vaniprevir (Merck) Sovaprevir (Achillion) Asunaprevir (BMS) NS3/NS4A structure Repositioning of helicase domain Self cleavage Lipid Bilayer Inactive Insertion of the Active carboxy-terminal tail Bartenschlager et al. -
2019 Icar Program & Abstracts Book
Hosted by the International Society for Antiviral Research (ISAR) ND International Conference 32on Antiviral Research (ICAR) Baltimore MARYLAND PROGRAM and USA Hyatt Regency BALTIMORE ABSTRACTS May 12-15 2019 ND TABLE OF International Conference CONTENTS 32on Antiviral Research (ICAR) Daily Schedule . .3 Organization . 4 Contributors . 5 Keynotes & Networking . 6 Schedule at a Glance . 7 ISAR Awardees . 10 The 2019 Chu Family Foundation Scholarship Awardees . 15 Speaker Biographies . 17 Program Schedule . .25 Posters . 37 Abstracts . 53 Author Index . 130 PROGRAM and ABSTRACTS of the 32nd International Conference on Antiviral Research (ICAR) 2 ND DAILY International Conference SCHEDULE 32on Antiviral Research (ICAR) SUNDAY, MAY 12, 2019 › Women in Science Roundtable › Welcome and Keynote Lectures › Antonín Holý Memorial Award Lecture › Influenza Symposium › Opening Reception MONDAY, MAY 13, 2019 › Women in Science Award Lecture › Emerging Virus Symposium › Short Presentations 1 › Poster Session 1 › Retrovirus Symposium › ISAR Award of Excellence Presentation › PechaKucha Event with Introduction of First Time Attendees TUESDAY, MAY 14, 2019 › What’s New in Antiviral Research 1 › Short Presentations 2 & 3 › ISAR Award for Outstanding Contributions to the Society Presentation › Career Development Panel › William Prusoff Young Investigator Award Lecture › Medicinal Chemistry Symposium › Poster Session 2 › Networking Reception WEDNESDAY, MAY 15, 2019 › Gertrude Elion Memorial Award Lecture › What’s New in Antiviral Research 2 › Shotgun Oral -
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Review Article Chronic Hepatitis C Infection in Children: Current Treatment and New Therapies Andrew Lee1,2*, Jeremy Rajanayagam1,3 and Mona Abdel-Hady1 1Birmingham Children’s Hospital, Liver Unit, Birmingham, United Kingdom; 2The University of Queensland, School of Medicine, Brisbane, Australia; 3University of Birmingham, School of Infection and Immunity, Birmingham, United Kingdom Abstract remains the most common method of infection in the developing world.1,2 The overall rate of spontaneous viral Viral hepatitis C is responsible for a large burden of disease clearance following childhood infection is low, with the worldwide. Treatment of hepatitis C infection is currently majority of children developing chronic hepatitis C (CHC) undergoing a revolution with the development of new direct (54–86%).2 The clinical course of CHC in children is usually acting antivirals that offer higher cure rates and fewer side silent, with mildly abnormal liver function tests (LFTs) and effects than other medications currently available. Treatment minimal inflammation and fibrosis on histology.2–4 options for children, although well-defined and evidence- Nevertheless, fibrosis tends to progress with time, culminat- based, are limited relative to adults as there are few trials ing in cirrhosis in 5–10% or hepatocellular carcinoma (HCC) regarding the use of these newly developed agents in in 2–5% in adulthood.2,3 Thus, continued efforts to effectively children. With so much optimism in the development of novel treat children and reduce the long-term health and social therapeutic options for hepatitis C, it is timely to review and consequences in pediatric CHC are justified. summarize the current standard of care treatment and indications for treatment of chronic hepatitis C in children. -
Unfolded Protein Response in Hepatitis C Virus Infection
REVIEW ARTICLE published: 20 May 2014 doi: 10.3389/fmicb.2014.00233 Unfolded protein response in hepatitis C virus infection Shiu-Wan Chan* Faculty of Life Sciences, The University of Manchester, Manchester, UK Edited by: Hepatitis C virus (HCV) is a single-stranded, positive-sense RNA virus of clinical Hirofumi Akari, Kyoto University, importance. The virus establishes a chronic infection and can progress from chronic Japan hepatitis, steatosis to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The Reviewed by: mechanisms of viral persistence and pathogenesis are poorly understood. Recently Ikuo Shoji, Kobe University Graduate School of Medicine, Japan the unfolded protein response (UPR), a cellular homeostatic response to endoplasmic Kohji Moriishi, University of reticulum (ER) stress, has emerged to be a major contributing factor in many human Yamanashi, Japan diseases. It is also evident that viruses interact with the host UPR in many different ways *Correspondence: and the outcome could be pro-viral, anti-viral or pathogenic, depending on the particular Shiu-Wan Chan, Faculty of Life type of infection. Here we present evidence for the elicitation of chronic ER stress in Sciences, The University of Manchester, Michael Smith HCV infection. We analyze the UPR signaling pathways involved in HCV infection, the Building, Oxford Road, various levels of UPR regulation by different viral proteins and finally, we propose several Manchester M13 9PT, UK mechanisms by which the virus provokes the UPR. e-mail: shiu-wan.chan@ manchester.ac.uk Keywords: hepatitis C virus, unfolded protein response, endoplasmic reticulum stress, hepacivirus, virus-host interaction INTRODUCTION (LDLs) and very low-density lipoproteins (VLDLs) to form the Hepatitis C virus (HCV) infection produces a clinically important lipoviroparticles (Andre et al., 2002).