4obc

Publication Abstract from PubMed

Resistance to the 2'-F-2'-C-methylguanosine monophosphate nucleotide HCV inhibitors PSI-352938 and PSI-353661 was associated with a combination of amino acid changes (S15G/C223H/V321I) within the genotype 2a NS5B RNA-dependent RNA polymerase. To understand the role of these residues in viral replication, we examined the effect of single and multiple point mutations on replication fitness and inhibition by a series of nucleotide analog inhibitors. An acidic residue at position 15 reduced replicon fitness, consistent with its proximity to the RNA template. Change of 223 to an acidic or large residue reduced replicon fitness, consistent with its proposed proximity to the incoming NTP. Change of 321 to a charged residue was not tolerated, consistent with its position within a hydrophobic cavity. This triple resistance mutation was specific to both genotype 2a and 2'-F-2'-C-methylguanosine inhibitors. A crystal structure of JFH-1 S15G/C223H/V321I NS5B exhibited rearrangement to a conformation potentially consistent with short primer-template RNA binding, which could suggest a mechanism of resistance accomplished through a change in the NS5B conformation, which was better tolerated by genotype 2a than other genotypes.

Molecular and structural basis for the roles of HCV polymerase NS5B amino acids 15, 223, and 321 in viral replication and drug resistance.,Lam AM, Edwards TE, Mosley RT, Murakami E, Bansal S, Lugo C, Bao H, Otto MJ, Sofia MJ, Furman PA Antimicrob Agents Chemother. 2014 Sep 2. pii: AAC.03847-14. PMID:25182647^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.