title: Evaluation of ITX 5061, a scavenger receptor B1 antagonist: resistance selection and activity in combination with other hepatitis C virus antivirals.
abstract: ITX 5061 is a scavenger receptor B1 antagonist that has entered phase 1 clinical trials in hepatitis C virus (HCV)-infected humans. We evaluated ITX 5061 in combination with interferon-α, ribavirin, and HCV protease and polymerase inhibitors in a genotype 2a infectious virus system. ITX 5061 is a potent inhibitor of HCV replication and is additive to synergistic with interferon-α, ribavirin, BILN2061, VX950, VX1, and 2'-C-methyladenosine. Resistance selection experiments were performed using a Jc1-FEO virus co-culture system and intermittent ITX 5061 exposure under neomycin selection. We identified a mutant virus with a substitution of aspartic acid for asparagine at the highly conserved position 415 in E2 (N415D). Introduction of this mutation into wild-type virus conferred high-level resistance to ITX 5061. There was no cross-resistance between ITX 5061 and HCV protease inhibitors or interferon-α. These results suggest that ITX 5061 is a promising compound for study in combination with other HCV inhibitors.
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Institute of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Haihong
authors.initials: H
authors.lastname: Zhu
authors.forename: Flossie
authors.initials: F
authors.lastname: Wong-Staal
authors.forename: Haekyung
authors.initials: H
authors.lastname: Lee
authors.forename: Andrew
authors.initials: A
authors.lastname: Syder
authors.forename: Jeffrey
authors.initials: J
authors.lastname: McKelvy
authors.forename: Robert T
authors.initials: RT
authors.lastname: Schooley
authors.forename: David L
authors.initials: DL
authors.lastname: Wyles
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D024882:Drug Resistance, Viral; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D020125:Mutation, Missense; D012254:Ribavirin / Q000494:pharmacology; D051122:Scavenger Receptors, Class B / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D012254:Ribavirin