,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 separa te study to be inhibitors of S-adenosylhomocysteine hydrolase and devo id of substrate activity with adenosine kinase and adenosine deaminase , were found in this study to inhibit vaccinia virus replication in mu rine L929 cells and to have reduced cytotoxicity compared with that of the parent compound. Aristeromycin was shown to produce cytocidal eff ects on murine L929 cells, whereas the synthetic analogues produced cy tostatic effects on cell growth. The antiviral effects of these synthe tic analogues are correlated with their ability to elevate the intrace llular ratio of S-adenosylhomocysteine/S-adenosylmethionine. These res ults confirm that S-adenosylhomocysteine hydrolase is the molecular ta rget which mediates the antiviral effects of aristeromycin and that tr ansformation of aristeromycin by cellular adenosine kinase mediates it s cytocidal properties.