(1'R,2'S,3'R)-9-(2',3'-DIHYDROXYCYCLOPENTAN-1'-YL)-ADENINE AND 3-DEAZA-ADENINE - ANALOGS OF ARISTEROMYCIN WHICH EXHIBIT POTENT ANTIVIRAL ACTIVITY WITH REDUCED CYTOTOXICITY

Two synthetic analogues of aristeromycin, which were shown in a separate study to be inhibitors of S-adenosylhomocysteine hydrolase and devoid of substrate activity with adenosine kinase and adenosine deaminase, were found in this study to inhibit vaccinia virus replication in murine L929 cells and to have reduced cytotoxicity compared with that of the parent compound. Aristeromycin was shown to produce cytocidal effects on murine L929 cells, whereas the synthetic analogues produced cytostatic effects on cell growth. The antiviral effects of these synthetic analogues are correlated with their ability to elevate the intracellular ratio of S-adenosylhomocysteine/S-adenosylmethionine. These results confirm that S-adenosylhomocysteine hydrolase is the molecular target which mediates the antiviral effects of aristeromycin and that transformation of aristeromycin by cellular adenosine kinase mediates its cytocidal properties.