Studies of the structure and function of Hepatitis C Virus (HCV) RNA-dependent RNA polymerase (RdRp)<br/>have broaden our understanding of HCV viral RNA replication and the mechanism of action of this RNA polymerase. These findings have encouraged the development of inhibitors of this target for antiviral therapy. Anti-HCV activity has been shown in-vivo with C-nucleosides containing a 2’-C-methyl (Me) substituent. The presence of the 2’-C-Me group prevents the chain elongation catalyzed by the RdRp NS5B. To further investigate this phenomenon, the synthesis of modified pseudouridines was performed using earlier developed strategies for the unmodified nucleoside. By coupling of the protected pyrimidine to a likewise protected 2’-C-methyl-D-ribono-lactone the C-nucleoside was formed. Subsequent reduction and ring closure generated alpha and/or beta- 2’-C-Me pseudouridines. Through the work presented here, this modified pseudouridine synthesis was optimized and will be utilized in the synthesis of other modifications of this naturally occurring nucleoside and evaluated for their antiviral activity. This will include conversion to substrates suitable for the monophosphate prodrug strategy.

Synthesis of 2’-C-methyl pseudouridines for the inhibition of HCV RNA-polymerase

254th National Meeting (2017)

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