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.

Fluoxazolevir 是一种基于芳基恶唑的丙型肝炎病毒 (HCV) 进入抑制剂。我们表明，氟恶唑韦通过结合 HCV 包膜蛋白 1 来阻止融合，从而抑制 HCV 与肝细胞的融合。十个氟恶唑韦耐药相关替换中有九个位于包膜蛋白 1 中，四个位于推定的融合肽中。小鼠、大鼠和狗的药代动力学研究表明，氟恶唑韦定位于肝脏。在感染了 HCV 基因型 1b、2a 或 3 的人源化嵌合小鼠中进行为期 4 周的氟恶唑韦腹膜内治疗，导致病毒血症减少 2-log，但没有耐药性证据。相比之下，daclatasvir 是一种已获批准的 HCV 药物，可抑制超过 3 log 的病毒血症，但与小鼠中出现耐药相关替代有关。使用氟恶唑韦和达卡他韦的联合治疗清除了小鼠的 HCV 基因型 1b 和 3。Fluoxazolevir 联合 glecaprevir 和 pibrentasvir 也能有效清除小鼠的多药耐药 HCV 复制。氟恶唑韦有望成为用于 HCV 治疗的下一代联合药物混合物。