Synthesis and antiviral activity of 5-substituted cytidine analogues: identification of a potent inhibitor of viral RNA-dependent RNA polymerases.
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.
Harki
Daniel A
DA
Department of Chemistry and Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Graci
Jason D
JD
Galarraga
Jessica E
JE
Chain
William J
WJ
Cameron
Craig E
CE
Peterson
Blake R
BR
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D003562:Cytidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D029822:Enterovirus B, Human / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D017955:Poliovirus / Q000187:drug effects / Q000201:enzymology; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C515132:5-nitrocytidine; D000998:Antiviral Agents; D003562:Cytidine; D012324:RNA-Dependent RNA Polymerase