Synthesis and antiviral activity of 5-substituted cytidine analogues: identification of a potent inhibitor of viral RNA-dependent RNA polymerases

J Med Chem. 2006 Oct 19;49(21):6166-9. doi: 10.1021/jm060872x.

Abstract

As part of our studies of lethal viral mutagens, a series of 5-substituted cytidine analogues were synthesized and evaluated for antiviral activity. Among the compounds examined, 5-nitrocytidine was effective against poliovirus (PV) and coxsackievirus B3 (CVB3) and exhibited greater activity than the clinically employed drug ribavirin. Instead of promoting viral mutagenesis, 5-nitrocytidine triphosphate inhibited PV RNA-dependent RNA polymerase (K(d) = 1.1 +/- 0.1 microM), and this inhibition is sufficient to explain the observed antiviral activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / pharmacology
  • Cytidine / analogs & derivatives*
  • Cytidine / chemical synthesis*
  • Cytidine / pharmacology
  • Enterovirus B, Human / drug effects
  • HeLa Cells
  • Humans
  • Poliovirus / drug effects
  • Poliovirus / enzymology
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • 5-nitrocytidine
  • Antiviral Agents
  • Cytidine
  • RNA-Dependent RNA Polymerase