Design and evaluation of a potential mutagen for Hepatitis C virus

Pyrrolopyrimidine nucleoside 1 was designed and synthesized as a potential mutagen for HCV. An in vitro HCV NS5B enzymatic assay indicated that pyrrolopyrimidine triphosphate acts as a CTP analog rather than a UTP analog. The SATE-prodrug of pyrrolopyrimidine monophosphate showed a weak inhibitory activity in an HCV replicon system (EC50 = 60 μM) and did not exhibit cytotoxicity (CC50 > 100 μM). Investigation of phosphorylation events using nucleoside kinases and LC–MS analysis revealed that the second phosphorylation step, from monophosphate ester to diphosphate ester, is unfavorable.

Potential mutagen for HCV that could serve as a cytidine or a uridine.Figure optionsDownload as PowerPoint slide