Evolution of HCV NS5B Nucleoside and Nucleotide Inhibitors

Abstract

Adenosine and cytidine analogs containing the 2′-C-methyl substituent were identified as initial hits from screening. These compounds displayed selective anti-HCV activity in a cell-based HCV replicon assay and, as their triphosphates, inhibited HCV NS5B polymerase enzyme in a cell-free assay. Since then, a number of new 2′-modified nucleoside analogs and nucleotide derivatives were synthesized and evaluated for direct inhibition of HCV replication. Potency, selectivity, and other drug-like properties were substantially optimized, and consequently more than a dozen compounds were advanced into preclinical and clinical evaluations. In the end, a prodrug of 2′-fluoro-2′-C-methyluridine monophosphate PSI-7977 (GS-7977, sofosbuvir) was approved for the treatment of chronic HCV infection.