Effects of chirality in 9-(2-hydroxy-3-nonyl)adenine upon deoxyribonucleic acid synthesis in herpes simplex virus-infected cells.

The antiherpes activities of erythro- and threo-9-(2-hydroxy-3-nonyl)adenines (EHNA and THNA) have been determined. All isomers inhibited the replication of herpes simplex virus (HSV) and inhibited DNA synthesis in HSV-infected cells. The two enantiomers of EHNA, (+)-EHNA and (-)-EHNA, displayed equal antiviral activities. This is in contrast to their activities as inhibitors of adenosine deaminase (ADA); (+)-EHNA is a 250-fold more potent inhibitor of ADA than (-)-EHNA [Bessodes et al. Biochem. Pharmac. 31, 879 (1982)]. The antiherpes activity of (+)-THNA was only slightly less than that of the EHNA isomers, whereas (-)-THNA was somewhat less active. The abilities of the four isomeres of EHNA and THNA to inhibit DNA synthesis in HSV-infected cells correlated with their abilities to inhibit virus multiplication. EHNA failed to inhibit HSV DNA polymerase activity in extracts from infected cells. Moreover, addition of EHNA to infected cells at 6 hr post-infection resulted in no inhibition of DNA synthesis. These results are inconsistent with a direct inhibition of macromolecular DNA synthesis by EHNA. Treatment of HSV-infected cells with EHNA produced a 2- to 4-fold decrease in levels of the four DNA precursors, deoxyribonucleoside 5'-triphosphates (dNTPs). This treatment had much less effect on dNTP levels in uninfected cells.