Mechanism of action of 1- -D-ribofuranosyl-1,2,4-triazole-3-carboxamide (Virazole), a new broad-spectrum antiviral agent.
The antiviral activity of the synthetic nucleoside, Virazole (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), against measles virus in Vero cell cultures was substantially reversed by xanthosine, guanosine, and to a slightly lesser extent by inosine. Virazole 5'-phosphate was subsequently found to be a potent competitive inhibitor of inosine 5'-phosphate dehydrogenase (IMP:NAD(+) oxidoreductase, EC 1.2.1.14) isolated from Escherichia coli (K(m) = 1.8 x 10(-5) M) with a K(i) of 2.7 x 10(-7) M. Guanosine 5'-phosphate (GMP) was a competitive inhibitor of this enzyme with a K(i) of 7.7 x 10(-5) M. Virazole 5'-phosphate was similarly active against IMP dehydrogenase isolated from Ehrlich ascites tumor cells, with a K(i) of 2.5 x 10(-7) M. The K(m) for this enzyme was 1.8 x 10(-5) M, and the K(i) for GMP was 2.2 x 10(-4) M. These results suggest that the antiviral activity of Virazole might be due to the inhibition of GMP biosynthesis in the infected cell at the step involving the conversion of IMP to xanthosine 5'-phosphate. This inhibition would consequently result in inhibition of the synthesis of vital viral nucleic acid.
D000469:Alkaline Phosphatase / Q000378:metabolism; D000577:Amides / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D002286:Carcinoma, Ehrlich Tumor / Q000201:enzymology; D002460:Cell Line; D004926:Escherichia coli / Q000201:enzymology; D006027:Glycosides / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006151:Guanosine / Q000494:pharmacology; D000882:Haplorhini; D007288:Inosine / Q000494:pharmacology; D007658:Ketone Oxidoreductases / Q000037:antagonists & inhibitors; D007668:Kidney; D008099:Liver / Q000378:metabolism; D008459:Measles virus / Q000187:drug effects*; D051379:Mice; D009705:Nucleosides / Q000494:pharmacology; D009711:Nucleotides / Q000494:pharmacology; D012263:Ribonucleosides / Q000494:pharmacology; D014230:Triazoles / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D014316:Tritium
D000577:Amides; D000998:Antiviral Agents; D006027:Glycosides; D009705:Nucleosides; D009711:Nucleotides; D012263:Ribonucleosides; D014230:Triazoles; D014316:Tritium; D006151:Guanosine; D007288:Inosine; D007658:Ketone Oxidoreductases; D000469:Alkaline Phosphatase