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A small-Molecule inhibitor of hepatitis C virus infectivity

Bush, CO and Pokrovskii, MV and Saito, R and Morganelli, P and Canales, E and Clarke, MO and Lazerwith, SE and Golde, J and Reid, BG and Babaoglu, K and Pagratis, N and Zhong, W and Delaney, WE and Paulson, MS and Beran, RKF (2014) A small-Molecule inhibitor of hepatitis C virus infectivity. Antimicrobial Agents and Chemotherapy. pp. 386-396.

Abstract

One of the most challenging goals of hepatitis C virus (HCV) research is to develop well-tolerated regimens with high cure rates across a variety of patient populations. Such a regimen will likely require a combination of at least two distinct direct-acting antivirals (DAAs). Combining two or more DAAs with different resistance profiles increases the number of mutations required for viral breakthrough. Currently, most DAAs inhibit HCV replication. We recently reported that the combination of two distinct classes of HCV inhibitors, entry inhibitors and replication inhibitors, prolonged reductions in extracellular HCV in persistently infected cells. We therefore sought to identify new inhibitors targeting aspects of the HCV replication cycle other than RNA replication. We report here the discovery of the first small-molecule HCV infectivity inhibitor, GS-563253, also called HCV infectivity inhibitor 1 (HCV II-1). HCV II-1 is a substituted tetrahydroquinoline that selectively inhibits genotype 1 and 2 HCVs withlow-nanomolar 50% effective concentrations. It was identified through a high-throughput screen and subsequent chemical optimization. HCV II-1 only permits the production and release of noninfectious HCV particles from cells. Moreover, infectious HCV is rapidly inactivated in its presence. HCV II-1 resistance mutations map to HCV E2. In addition, HCV-II prevents HCV endosomal fusion, suggesting that it either locks the viral envelope in its prefusion state or promotes a viral envelope conformation change incapable of fusion. Importantly, the discovery of HCV II-1 opens up a new class of HCV inhibitors that prolong viral suppression by HCV replication inhibitors in persistently infected cell cultures. 2014, American Society for Microbiology. All Rights Reserved

Item Type: Article
Additional Information: NIBR author: Lazic, S institute: NIBR- address only contributor address: (Bush, Saito, Morganelli, Canales, Clarke, Lazerwith, Pagratis, Delaney, Paulson, Beran) Gilead Sciences, Inc., Foster City, CA, United States (Pokrovskii) New York University Sackler Institute of Biomedical Sciences, New York, United States (Golde) Agilent Technologies Inc., Santa Clara, CA, United States (Reid) University of Colorado School of Pharmacy, Aurora, CO, United States (Babaoglu) Merck Research Laboratories, West Point, PA, United States (Zhong) Antiviral Research, Novartis Institutes for Biomedical Research, Emeryville, CA, United States
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/22641

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