Dual-action mechanism of viramidine functioning as a prodrug and as a catabolic inhibitor for ribavirin.
An investigational nucleoside analogue drug, viramidine, has recently emerged as a potentially safer alternative to ribavirin for the treatment of hepatitis C viral infection. We have reported that viramidine mainly functions as a prodrug of ribavirin that is enriched in the liver. This in vitro study further explores viramidine's activity against nucleoside phosphorylase, a host enzyme that is responsible for phosphorolysis of ribavirin in vivo. Our experiments show that viramidine inhibits ribavirin phosphorolysis with a K(i) of 2.5 microM. This result suggests that viramidine may act through a dual-action mechanism by serving as a prodrug of ribavirin and concomitantly as an inhibitor for nucleoside phosphorylase catabolism of ribavirin.
Wu
Jim Zhen
JZ
Drug Discovery, R&D, Valeant Pharmaceuticals International, 3300 Hyland Ave., Costa Mesa, CA 92626, USA. jwu@valeant.com
Larson
Gary
G
Hong
Zhi
Z
D000998:Antiviral Agents / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D002855:Chromatography, Thin Layer; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D006005:Phosphorylases / Q000097:blood / Q000378:metabolism; D011355:Prodrugs / Q000494:pharmacology*; D012254:Ribavirin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*
D000998:Antiviral Agents; D011355:Prodrugs; D012254:Ribavirin; D006005:Phosphorylases; C026956:taribavirin