Millions of people worldwide are affected by the hepatitis C virus (HCV). The current treatment is not only long but has limited efficacy and causes numerous side effects1; hence the need of more efficient therapies. The recent discovery of INX-189, a phosphoramidate of 2'-C-methyl-6-O-methylguanosine, targeting the RNA dependant RNA polymerase (RdRp) and showing nanomolar potency (EC50=0.008 �M), led to nucleobase modifications of the poorly active parent nucleoside (EC50=3 �M) in order to investigate potential inhibitory activity against RdRp2 by delivering inside the cells a new nucleoside analogue.  A range of new 8-modified nucleosides was synthesised, and their anti-HCV activity evaluated. The ProTide approach developed in our lab was then applied to improve the cellular uptake and to by-pass the first phosphorylation step required for delivery of the nucleoside monophosphate. Inhibitory activity in HCV replicon assay and toxicity are reported. 1  M.P. Walker & al., Antivir. Chem. Chemother., 2003, 14, 1-21.  2 C. McGuigan & al., BMCL, 2010, 4850-4854.

Novel 8-modified 2'-C-methyl-6-O-methylguanosine nucleosides and phosphoramidates for the treatment of hepatitis C virus

244th National Meeting (2012)

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