Open AccessFluoxazolevir inhibits hepatitis C virus infection in humanized chimeric mice by blocking viral membrane fusion
Author(s) -
D. Christopher,
Michio Imamura,
Daniel C. Talley,
Adam Rolt,
Xin Xu,
Amy Q. Wang,
Daniel Le,
Takuro Uchida,
Mitsutaka Osawa,
Yuji Teraoka,
Kelin Li,
Xin Hu,
Seung Bum Park,
Nishanth Chalasani,
Parker Irvin,
Andrés E. Dulcey,
Noel Southall,
Juan Marugán,
Zongyi Hu,
Kazuaki Chayama,
Kevin J. Frankowski,
T. Jake Liang
Publication year - 2020
Publication title -
nature microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.305
H-Index - 79
ISSN - 2058-5276
DOI - 10.1038/s41564-020-0781-2
Subject(s) - daclatasvir , virology , hepatitis c virus , entry inhibitor , viral envelope , virus , enfuvirtide , fusion protein , viral replication , medicine , biology , pharmacology , viral entry , immunology , antibody , recombinant dna , epitope , gp41 , gene , biochemistry , ribavirin
Fluoxazolevir is an aryloxazole-based entry inhibitor of hepatitis C virus (HCV). We show that fluoxazolevir inhibits fusion of HCV with hepatic cells by binding HCV envelope protein 1 to prevent fusion. Nine of ten fluoxazolevir resistance-associated substitutions are in envelope protein 1, and four are in a putative fusion peptide. Pharmacokinetic studies in mice, rats and dogs revealed that fluoxazolevir localizes to the liver. A 4-week intraperitoneal regimen of fluoxazolevir in humanized chimeric mice infected with HCV genotypes 1b, 2a or 3 resulted in a 2-log reduction in viraemia, without evidence of drug resistance. In comparison, daclatasvir, an approved HCV drug, suppressed more than 3 log of viraemia but is associated with the emergence of resistance-associated substitutions in mice. Combination therapy using fluoxazolevir and daclatasvir cleared HCV genotypes 1b and 3 in mice. Fluoxazolevir combined with glecaprevir and pibrentasvir was also effective in clearing multidrug-resistant HCV replication in mice. Fluoxazolevir may be promising as the next generation of combination drug cocktails for HCV treatment.