학술논문
2'-Chloro,2'-fluoro Ribonucleotide Prodrugs with Potent Pan-genotypic Activity against Hepatitis C Virus Replication in Culture.
Document Type
Article
Author
Shaoman Zhou; Mahmoud, Sawsan; Peng Liu; Longhu Zhou; Ehteshami, Maryam; Bassit, Leda; Tao, Sijia; Domaoal, Robert A.; Sari, Ozkan; De Schutter, Coralie; Amiralaei, Sheida; Khalil, Ahmed; Russell, Olivia Ollinger; McBrayer, Tamara; Whitaker, Tony; Abou-Taleb, Nageh; Amblard, Franck; Coats, Steven J.; Schinazi, Raymond F.
Source
Subject
*NUCLEOSIDES
*DRUG resistance in microorganisms
*PHOSPHORAMIDATES
*POLYMERASES
*RNA polymerases
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Language
ISSN
0022-2623
Abstract
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. [ABSTRACT FROM AUTHOR]