Synergistic Antiviral Activity of Inhibitors of S-Adenosylhomocysteine Hydrolase and Ribavirin

Abstract

(1′R,2′S,3′R)-9-(2′,3′-Dihydroxycycloperrt-4′-en-1′-yl)-adenine (DHCeA) and -3-deazaadenine (3-deaza-DHCeA), which are potent inhibitors of S-adenosylho-mocysteine (AdoHcy) hydrolase, and ribavirin, which is an inhibitor of IMP-dehydrogenase, were found in this study to have synergistic effects on inhibiting vaccinia virus replication in murine L929 cells without creating a synergistic effect on cellular toxicity. Thus, the antiviral effectiveness of this drug combination was 5–10× higher than the antiviral effectiveness observed with the AdoHcy hydrolase inhibitors alone. Ribavirin does not alter the ability of DHCeA and 3-deaza-DHCeA to elevate the intracellular AdoHcy/S-adeno-sylmethionine (AdoMet) ratio. Increases in this ratio were shown earlier to correlate with the antiviral effects of these carbocyclic nucleosides. Ribavirin was also shown to significantly reduce the cellular level of GTP, which is consistent with its activity as an inhibitor of IMP-dehydrogenase and its proposed mechanism of antiviral action, inhibiting the formation of the ‘capped methylated structure’ at the 5′-end of viral mRNA.