Kinetic Basis for Selective Inhibition of Hepatitis C Virus RNA‐Dependent RNA Polymerase by Nucleoside Analogs

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The Hepatitis C Virus (HCV) infects an estimated 71 million people worldwide. Currently, there is no vaccine available to treat or prevent HCV infections. Nucleoside analogs (NA) with a modification on the 2′‐carbon are a group of drugs that target the HCV RNA‐dependent RNA polymerase, NS5B. Among these nucleoside analogs are the prodrug Mericitabine and Sofosbuvir which get metabolized to 2′‐fluoro‐2′‐C‐methylcytidine‐5′‐triphosphate and 2′fluoro‐2′‐C‐methyluridine‐5′‐triphosphate, respectively. These compounds work by mimicking natural nucleotides and competing for binding and incorporation during the replication of the HCV genome. Once incorporated they act as chain terminators by preventing further elongation of the nascent RNA strand. Recently, it has been shown that NA can be excised by a nucleotide‐mediated excision reaction which rescues RNA synthesis. In this study we use transient‐state kinetics to understand the mechanism of inhibition for two CTP analogs and a UTP analog. The results demonstrate that while CTP analogs are readily incorporated and excised, UTP and the UTP analogs efficiently incorporated but are resistant to excision.Support or Funding InformationThis work was supported by funding from the NIHThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.