title: A small-molecule inhibitor of hepatitis C virus infectivity.
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 with low-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.
authors.affiliation: Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: Caroline O
authors.initials: CO
authors.lastname: Bush
authors.forename: Maria V
authors.initials: MV
authors.lastname: Pokrovskii
authors.forename: Roland
authors.initials: R
authors.lastname: Saito
authors.forename: Philip
authors.initials: P
authors.lastname: Morganelli
authors.forename: Eda
authors.initials: E
authors.lastname: Canales
authors.forename: Michael O
authors.initials: MO
authors.lastname: Clarke
authors.forename: Scott E
authors.initials: SE
authors.lastname: Lazerwith
authors.forename: Justin
authors.initials: J
authors.lastname: Golde
authors.forename: Brian G
authors.initials: BG
authors.lastname: Reid
authors.forename: Kerim
authors.initials: K
authors.lastname: Babaoglu
authors.forename: Nikos
authors.initials: N
authors.lastname: Pagratis
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhong
authors.forename: William E
authors.initials: WE
authors.lastname: Delaney
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Paulson
authors.forename: Rudolf K F
authors.initials: RK
authors.lastname: Beran
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D024882:Drug Resistance, Viral; D016174:Hepacivirus / Q000187:drug effects* / Q000378:metabolism; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D017361:Viral Nonstructural Proteins