386213-38-3Relevant articles and documents
Evaluation of the role of three candidate human kinases in the conversion of the hepatitis C virus inhibitor 2′-C-methyl-cytidine to its 5′-monophosphate metabolite
Golitsina, Nina L.,Danehy Jr., Francis T.,Fellows, Ross,Cretton-Scott, Erika,Standring, David N.
experimental part, p. 470 - 481 (2010/12/19)
Nucleoside analogs are effective inhibitors of the hepatitis C virus (HCV) in the clinical setting. One such molecule, 2′-C-methyl-cytidine (2′-MeC), entered clinical development as NM283, a valine ester prodrug form of 2′-MeC possessing improved oral bioavailability. To be active against HCV, 2′-MeC must be converted to 2′-MeC triphosphate which inhibits NS5B, the HCV RNA-dependent RNA polymerase. Conversion of 2′-MeC to 2′-MeC monophosphate is the first step in 2′-MeC triphosphate production and is thought to be the rate-limiting step. Here we investigate which of three possible enzymes, deoxycytidine kinase (dCK), uridine-cytidine kinase 1 (UCK1), or uridine-cytidine kinase 2 (UCK2), mediate this first phosphorylation step. Purified recombinant enzymes UCK2 and dCK, but not UCK1, could phosphorylate 2′-MeC in vitro. However, siRNA knockdown experiments in three human cell lines (HeLa, Huh7 and HepG2) defined UCK2 and not dCK as the key kinase for the formation of 2′-MeC monophosphate in cultured human cells. These results underscore the importance of confirming enzymatic kinase data with appropriate cell-based assays. Finally, we present data suggesting that inefficient phosphorylation by UCK2 likely limits the antiviral activity of 2′-MeC against HCV. This paves the way for the use of a nucleotide prodrug approach to overcome this limitation.
Cyclic phosphoramidates as prodrugs of 2′-C-methylcytidine
Meppen, Malte,Pacini, Barbara,Bazzo, Renzo,Koch, Uwe,Leone, Joseph F.,Koeplinger, Kenneth A.,Rowley, Michael,Altamura, Sergio,Di Marco, Annalise,Fiore, Fabrizio,Giuliano, Claudio,Gonzalez-Paz, Odalys,Laufer, Ralph,Pucci, Vincenzo,Narjes, Frank,Gardelli, Cristina
experimental part, p. 3765 - 3770 (2009/12/24)
The currently approved treatment for hepatitis C virus infections is a combination of Ribavirin and pegylated Interferon. It leads to a sustained virologic response in approximately only half of the patients treated. For this reason there is an urgent need of new therapeutic agents. 2′-C-Methylcytidine is the first nucleoside inhibitor of the HCV NS5B polymerase that was efficacious in reducing the viral load in patients infected with HCV. The application of a monophosphate prodrug approach based on unprecedented cyclic phosphoramidates is reported. Our SAR studies led to compounds that are efficiently converted to the active triphosphate in human hepatocytes.
