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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. -
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 -
Polymerase Inhibitors
New Therapeutic Strategies: Polymerase Inhibitors 6th Paris Hepatitis Conference 14th - 15th January, 2013 Stefan Zeuzem Goethe University Hospital Frankfurt, Germany Direct antiviral targets C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B NS5A NS3 Bifunctional NS5B RNA-dependent protease / helicase RNA polymerase Antiviral Activity of DAAs Vary Among and Within Classes 3-14 day monotherapy in genotype 1 patients NS3 protease inhibitors NS5A inhibitors non-nucleoside inhibitors nucleos/tide inhibitors Median or Mean HCV RNA Decline (log IU/mL) Median or Mean HCV RNA BCP, boceprevir; TVP, telaprevir. Sarrazin C, Zeuzem S. Gastroenterology. 2010;138:447-62. Characteristics of DAAs and HTAs Efficacy Genotype Barrier to independency resistance NS3/4A (protease inhibitors) +++ ++ + - ++ NS5A +++ + - ++ + - ++ NS5B (nucleosides) + - +++ +++ +++ NS5B (non-nucleosides) + - ++ + + Cyclophilin Inhibitors ++ +++ +++ Nucleosidic polymerase inhibitors • RG-7128 (Mericitabine): moderate efficacy, safe • GS-7977 (Sofosbuvir): high efficacy, safe • Alios-2200 = VX135: high efficacy, early phase 2 • NM-283 (Valopicitabine): low efficacy, GI toxicity > • R-1626: moderate efficacy, lymphopenia > • INX-189 = BMS-986094: high efficacy, cardiac tox. > • IDX-184: moderate efficacy, on hold • PSI-938: high efficacy, hepatotoxicity > Nucleosidic polymerase inhibitors • RG-7128 (Mericitabine): moderate efficacy, safe • GS-7977 (Sofosbuvir): high efficacy, safe • Alios-2200 = VX135: high efficacy, early phase 2 • NM-283 (Valopicitabine): low efficacy, GI toxicity > • R-1626: moderate efficacy, lymphopenia > • INX-189 = BMS-986094: high efficacy, cardiac tox. > • IDX-184: moderate efficacy, on hold • PSI-938: high efficacy, hepatotoxicity > PROPEL study: Efficacy and safety of MCB + PR in G1/4 treatment-naive patients . Mericitabine nucleoside analog MCB 500 mg 12 wk (RVR-guided) polymerase inhibitor 100 MCB 1000 mg 8 wk (RVR-guided) MCB 1000 mg 12 wk (RVR-guided) . -
Review Resistance to Mericitabine, a Nucleoside Analogue Inhibitor of HCV RNA-Dependent RNA Polymerase
Antiviral Therapy 2012; 17:411–423 (doi: 10.3851/IMP2088) Review Resistance to mericitabine, a nucleoside analogue inhibitor of HCV RNA-dependent RNA polymerase Jean-Michel Pawlotsky1,2*, Isabel Najera3, Ira Jacobson4 1National Reference Center for Viral Hepatitis B, C and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France 2INSERM U955, Créteil, France 3Roche, Nutley, NJ, USA 4Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA *Corresponding author e-mail: [email protected] Mericitabine (RG7128), an orally administered prodrug passage experiments. To date, no evidence of genotypic of PSI-6130, is the most clinically advanced nucleoside resistance to mericitabine has been detected by popula- analogue inhibitor of the RNA-dependent RNA poly- tion or clonal sequence analysis in any baseline or on- merase (RdRp) of HCV. This review describes what has treatment samples collected from >600 patients enrolled been learnt so far about the resistance profile of mericit- in Phase I/II trials of mericitabine administered as mon- abine. A serine to threonine substitution at position 282 otherapy, in combination with pegylated interferon/ (S282T) of the RdRp that reduces its replication capacity ribavirin, or in combination with the protease inhibitor, to approximately 15% of wild-type is the only variant danoprevir, for 14 days in the proof-of-concept study of that has been consistently generated in serial in vitro interferon-free therapy. Introduction The approval of boceprevir and telaprevir [1,2], the first HCV variants are selected and grow when the inter- inhibitors of the non-structural (NS) 3/4A (NS3/4A) feron response is inadequate [3,4,6]. -
Inhibitor-Based Therapeutics for Treatment of Viral Hepatitis
Review Article Inhibitor-Based Therapeutics for Treatment of Viral Hepatitis Debajit Dey and Manidipa Banerjee* Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, India Abstract When such inflammation, as manifested in symptoms such as jaundice, nausea, abdominal pain, malaise etc, is caused Viral hepatitis remains a significant worldwide threat, in spite by viral infections, the condition is referred to as viral hepatitis.1 of the availability of several successful therapeutic and vacci- Five hepatotropic viruses – named hepatitis A, B, C, D and nation strategies. Complications associated with acute and E viruses – target liver cells in humans and cause acute and chronic infections, such as liver failure, cirrhosis and hepato- chronic hepatitis. In addition, other viruses such as the cellular carcinoma, are the cause of considerable morbidity adenovirus, cytomegalovirus (CMV) and Epstein-Barr virus and mortality. Given the significant burden on the healthcare (EBV), occasionally cause symptoms of hepatitis.2 system caused by viral hepatitis, it is essential that novel, While an acute infection in healthy, immunocompetent more effective therapeutics be developed. The present review individuals is cleared spontaneously, complications like cir- attempts to summarize the current treatments against viral rhosis, hepatocellular carcinoma (HCC) and fulminant hepatic hepatitis, and provides an outline for upcoming, promising failure (FHF) may arise in immunocompromised individuals, new therapeutics. Development of novel therapeutics requires due to associated secondary reasons such as existing infec- an understanding of the viral life cycles and viral effectors in tions, alcohol abuse, or genetic predisposition.1,3 HCC, the molecular detail. As such, this review also discusses virally- third leading cause of cancer-related deaths worldwide,4 is encoded effectors, found to be essential for virus survival closely associated with hepatitis B virus (HBV) infections. -
Structural & Functional Characterization of the Dengue Virus Non
This document is downloaded from DR‑NTU (https://dr.ntu.edu.sg) Nanyang Technological University, Singapore. Structural & functional characterization of the dengue virus non‑structural protein 5 (NS5) Soh, Sherryl Tingjin 2018 Soh, S. T. (2018). Structural & functional characterization of the dengue virus non‑structural protein 5 (NS5). Doctoral thesis, Nanyang Technological University, Singapore. http://hdl.handle.net/10356/73218 https://doi.org/10.32657/10356/73218 Downloaded on 06 Oct 2021 23:07:19 SGT STRUCTURAL & FUNCTIONAL CHARACTERIZATION OF THE DENGUE VIRUS NON-STRUCTURAL PROTEIN 5 (NS5) SOH TINGJIN SHERRYL SCHOOL OF BIOLOGICAL SCIENCES 2017 STRUCTURAL & FUNCTIONAL CHARACTERIZATION OF THE DENGUE VIRUS NON-STRUCTURAL PROTEIN 5 (NS5) SOH TINGJIN SHERRYL School of Biological Sciences A thesis submitted to the Nanyang Technological University in partial fulfilment of the requirement for the degree of Doctor of Philosophy 2017 Acknowledgements Acknowledgements First and foremost, I would like to express my deepest gratitude to both my supervisors, Associate Professor Julien Lescar in NTU and Dr Lim Siew Pheng in Novartis Institute for Tropical Diseases (NITD), for their continuous guidance, encouragement and intense patience throughout my graduate education. Their expertise, meticulous attention and support had been greatly beneficial to me and to the success of my project. I am grateful to my colleagues in NITD, especially Ms Seh Cheah Chen and Dr Shan Chao who generously shared their knowledge and provided me with ample support and assistance. I would also like to thank my colleagues in NTU, especially Dr El Sahili Abbas and Ms Grace Chan Kar Yarn, who had rendered me with extensive help and advices for my crystallography experiments in NTU. -
Mechanisms of Substrate Recognition by HCV NS3/4A Protease Provide Insights Into Drug Resistance: a Dissertation
University of Massachusetts Medical School eScholarship@UMMS GSBS Dissertations and Theses Graduate School of Biomedical Sciences 2011-05-31 Mechanisms of Substrate Recognition by HCV NS3/4A Protease Provide Insights Into Drug Resistance: A Dissertation Keith P. Romano University of Massachusetts Medical School Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/gsbs_diss Part of the Amino Acids, Peptides, and Proteins Commons, Biochemistry, Biophysics, and Structural Biology Commons, Chemical Actions and Uses Commons, Digestive System Diseases Commons, Pharmaceutical Preparations Commons, Therapeutics Commons, Virology Commons, Virus Diseases Commons, and the Viruses Commons Repository Citation Romano KP. (2011). Mechanisms of Substrate Recognition by HCV NS3/4A Protease Provide Insights Into Drug Resistance: A Dissertation. GSBS Dissertations and Theses. https://doi.org/10.13028/2bmp-kp97. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/554 This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in GSBS Dissertations and Theses by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. MECHANISMS OF SUBSTRATE RECOGNITION BY HCV NS3/4A PROTEASE PROVIDE INSIGHTS INTO DRUG RESISTANCE A Dissertation Presented By Keith Patrick Romano Submitted to the Faculty of the University of Massachusetts Graduate School of Biomedical Sciences, Worcester In partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY May 31, 2011 Biochemistry and Molecular Pharmacology MECHANISMS OF SUBSTRATE RECOGNITION BY HCV NS3/4A PROTEASE PROVIDE INSIGHTS INTO DRUG RESISTANCE A Dissertation Presented By Keith Patrick Romano The signatures of the Dissertation Defense Committee signify completion and approval as to style and content of the Dissertation. -
A Phase 2 Study of Filibuvir in Combination with Pegylated IFN Alfa and Ribavirin for Chronic HCV
ORIGINAL ARTICLE July-August, Vol. 13 No. 4, 2014: 364-375 A phase 2 study of filibuvir in combination with pegylated IFN alfa and ribavirin for chronic HCV Maribel Rodriguez-Torres,* Eric M. Yoshida,** Patrick Marcellin,*** Subasree Srinivasan,****, Vivek S. Purohit,**** Cunshan Wang,**** Jennifer L. Hammond**** * Fundación de Investigación and San Juan Bautista School of Medicine, San Juan, Puerto Rico, USA. ** University of British Columbia and Vancouver General Hospital, Vancouver, B.C. Canada. *** Service d’Hépatologie, Hôpital Beaujon, Université Paris-Diderot, Clichy, France. **** Pfizer, Global Innovative Pharma Business Unit, Groton, CT, and Collegeville, PA, USA. No longer affiliated with Pfizer. ABSTRACT Objectives. Filibuvir is a non-nucleoside inhibitor of hepatitis C virus (HCV) polymerase. This study evalua- ted the safety and efficacy of filibuvir plus pegylated interferon alfa-2a (pegIFN)/ribavirin. Material and methods. Treatment-naïve, HCV genotype-1 patients were randomized to receive filibuvir 300 or 600 mg twice daily (BID) or placebo plus pegIFN (180 μg/wk) and ribavirin (1,000/1,200 mg BID) for 24 weeks. Filibu- vir patients who achieved defined response through week 24 discontinued therapy at week 24. All other patients continued on open-label pegIFN/ribavirin through week 48. The primary endpoint was the propor- tion of patients who achieved sustained virologic response (SVR) defined as HCV RNA < 15 IU/mL at end of treatment (weeks 24 or 48) and week 72. Results. Overall, 288 patients were randomized and treated. SVR was achieved by 41.7, 39.6, and 45.8% of patients in the filibuvir 300 mg, 600 mg, and placebo arms, respec- tively. -
Stembook 2018.Pdf
The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.