2′-Chloro,2′-fluoro Ribonucleotide Prodrugs with Potent Pan-genotypic Activity against Hepatitis C Virus Replication in Culture

Pan-genotypic
nucleoside HCV inhibitors display a high genetic
barrier to drug resistance and are the preferred direct-acting agents
to achieve complete sustained virologic response in humans. Herein,
we report, the discovery of a β-d-2′-Cl,2′-F-uridine
phosphoramidate nucleotide 16, as a nontoxic pan-genotypic
anti-HCV agent. Phosphoramidate 16 in its 5′-triphosphate
form specifically inhibited HCV NS5B polymerase with no marked inhibition
of human polymerases and cellular mitochondrial RNA polymerase. Studies
on the intracellular half-life of phosphoramidate 16-TP
in live cells demonstrated favorable half-life of 11.6 h, suggesting
once-a-day dosing. Stability in human blood and favorable metabolism
in human intestinal microsomes and liver microsomes make phosphoramidate 16 a prospective candidate for further studies to establish
its potential value as a new anti-HCV agent.

泛基因型核苷类丙型肝炎病毒（Hepatitis C Virus, HCV）抑制剂具有较高的耐药基因屏障，是实现人类完全持续病毒学应答的优选直接抗病毒药物。本研究报道了β-D-2′-氯-2′-氟尿苷磷酰胺酸核苷酸16的发现，该化合物为无毒的泛基因型抗HCV药物。其5′-三磷酸形式的磷酰胺酸酯16可特异性抑制HCV NS5B聚合酶，对人类聚合酶及细胞线粒体RNA聚合酶无显著抑制作用。针对活细胞内磷酰胺酸酯16-TP的细胞内半衰期研究显示，其半衰期达11.6小时，提示可采用每日一次给药方案。该化合物在人血液中稳定性良好，且在人肠道微粒体与肝微粒体中代谢特性优异，因此有望成为后续研究的候选化合物，以验证其作为新型抗HCV药物的潜在价值。