Structure-activity relationships of [2′,5′-bis-O-(tert- butyldimethylsilyl)-β-D-ribofuranosyl]-3′-spiro-5″-(4″- amino-1″,2″-oxathiole-2″,2″-dioxide)thymine derivatives as inhibitors of HIV-1 reverse transcriptase dimerization

The polymerase activity of HIV-1 reverse transcriptase (RT) is entirely dependent on the heterodimeric structure of the enzyme. Accordingly, RT dimerization represents a target for the development of a new therapeutic class of HIV inhibitors. We previously demonstrated that the N-3-ethyl derivative of 2′,5′-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl] -3′-spiro-5″-(4″-amino-1″,2″-oxathiole-2″, 2″-dioxide)-thymine (TSAO-T) destabilizes the inter-subunit interactions of HIV-1 RT [Sluis-Cremer, N.; Dmietrinko, G. I.; Balzarini, J.; Camarasa, M.-J.; Parniak, M. A. Biochemistry 2000, 39, 1427-1433]. In the current study, we evaluated the ability of 64 TSAO-T derivatives to inhibit RT dimerization using a novel screening assay. Five derivatives were identified with improved activity compared to TSAO-T. Four of these harbored hydrophilic or aromatic substituents at the N3 position. Furthermore, a good correlation between the ability of the TSAO-T derivatives to inhibit RT dimerization and the enzyme's polymerase activity was also observed. This study provides an important framework for the rational design of more potent inhibitors of RT dimerization.