The importance of IMP dehydrogenase inhibition in the broad spectrum antiviral activity of ribavirin and selenazofurin

Abstract

The nucleosides ribavirin, selenazofurin, tiazofurin and bredinin all exhibit the lowering of guanylate pools in vitro and in vivo by the inhibition of IMP dehydrogenase. However, each of these nucleosides has a separate profile of antiviral and antitumor activity. The IMP dehydrogenase inhibition in the case of ribavirin and bredinin appears to be due to the nucleoside 5'-monophosphate and in the case of selenazofurin and tiazofurin to the NAD analogs formed intracellularly. With regard to the antiviral activity of these nucleosides, although selenazofurin was the most potent antiviral agent in vitro, its antiviral activity was also most readily reversed by exogenous guanosine. The antiviral effects of ribavirin were only partially reversed under the conditions studied. These and related studies show that each of these nucleosides form nucleotide metabolites which act as enzyme inhibitors at additional sites other than IMP dehydrogenase. As in the case of ribavirin such inhibition of IMP dehydrogenase may result in an increased "self potentiation" by the lowering of guanylate pools in those instances where guanylate analogs are involved as inhibitors of viral specific or viral induced enzymes. Further studies should more clearly elucidate the importance of the simultaneous inhibition of various enzyme sites by different metabolic nucleotide forms of the same nucleoside analog.