The Effect of Absolute Configuration on the Anti-HIV and Anti-HBV Activity of Nucleoside Analogues

Abstract

This review concerns the effect of stereoisomerism on the selective activity of anti-HIV and anti-HBV nucleoside analogues. The synthesis of a number of nucleoside analogues with anti-HIV and anti-HBV activity yields mixtures of 1-β-D and 1-β-L stereoisomers. Anti-HIV and anti-HBV activity is associated primarily with one of the two enantiomers and the more potent activity does not always reside with the 1-β-D configuration characteristic of natural nucleosides. In the case of HIV, the origin of this stereoselectivity appears to be the result of differential metabolism of the analogues and not due to differential inhibition of the target enzyme; the HIV reverse transcriptase. However, mutations at position 184 of the HIV-RT does result in stereoselective inhibition of the enzyme. On the other hand, with HBV, there is also a stereoselective inhibition of the HBV DNA polymerase, where the 5′-triphosphate of the 1-β-L enantiomer is the more potent inhibitor.