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 (EC(50)=60 microM) and did not exhibit cytotoxicity (CC(50)>100 microM). 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.
Koh
Yung-Hyo
YH
Valeant Pharmaceutical Research & Development, 3300 Hyland Ave., Costa Mesa, CA 92626, USA. ykoh@andreabiosciences.com
Shim
Jae Hoon
JH
Girardet
Jean-Luc
JL
Hong
Zhi
Z
D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D009153:Mutagens / Q000494:pharmacology*; D010766:Phosphorylation; D014779:Virus Replication / Q000187:drug effects
D009153:Mutagens