12th International HIV Drug Resistance Workshop 10–14 June 2003, Cabo del Sol, Los Cabos, Mexico

BACKGROUND: The development of viral resistance to lamivudine (3TC) prompted the discovery of nucleosides with activity against HIV isolates containing the 3TC resistance mutation. Since the finding that β–D-dioxolane-2,6-diaminopurine (DAPD or amdoxovir) is active against zidovudine (AZT)- as well as 3TC-resistant mutants, several nucleosides with a dioxolane moiety have been synthesized. Among the series of dioxolane nucleosides, the thymidine and 5-fluorocytidine analogues showed potent anti-HIV activity against 3TC-resistant mutant reverse transcriptase. Thus, it is of great interest to understand the role of dioxolane moiety in the anti-HIV activity against 3TC-resistant mutant.

METHODS: Various D-dioxolane nucleoside triphosphates and 3TC triphosphate were docked into the active site of wild-type as well as 3TC-resistant reverse transcriptase, and the resulting complexes were energy-minimized. The M184V mutation imposes steric hindrances to the incoming nucleoside triphosphates as well as the nearby primer chain. Therefore, if the nucleoside triphosphate–reverse transcriptase complex cannot provide enough conformational flexibility to escape from the steric hindrance, it results in an abortive binding state.

RESULTS: Our molecular modeling studies indicated that D-dioxolane nucleoside triphosphates–reverse transcriptase complexes, unlike 3TC triphosphate–reverse transcriptase complex, are not sterically hindered by the bulky side chain of Val184, and maintain the favourable binding modes through the interaction of 3’-oxygen with active site residues such as Arg72 or Tyr115. However, the way in which each complexes resolve the steric hindrance of Val184 with the primer strand without deforming the binding mode, was quite different depending upon the heterocyclic bases attached: slight rotation of Val184 into Tyr183 in dioxolane-T, conformational change in sugar moiety of the primer residue (from 3’-exo to 3’-endo) in 5-Fdioxoloane-C and rotation of Val184 into the nucleoside triphosphate binding site with concurrent conformational change in the dioxolane moiety (from 3’-endo to 3’-exo) in dioxolane G.

CONCLUSION: The molecular modeling studies show that the dioxolane moiety of D-dioxolane nucleosides enables the nucleoside triphosphate to strongly bind to the active site of 3TC-resistant mutant reverse transcriptase without steric hindrance with Val184. It is noteworthy that, depending upon the attached heterocyclic moiety, the binding modes of each dioxolane nucleoside triphosphate is different. This work would lead to the discovery of additional dioxolane with improved activity against 184V mutants.

Supported by NIH AI32351,AI25899 and Veterans Affairs).

PRESENTING AUTHOR: CK Chu

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2003-07-08
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