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Background:  The majority of AIDS patients are currently taking nucleosides as part of combination therapy. Therefore, the development of nucleoside-resistant mutants of HIV-1 is a serious problem for the management of HIV infection.

Methods:  Since the discovery that β-D-dioxolane-2, 6-diaminopurine (DAPD or Amdoxovir) is active against zidovudine- (AZT-) and lamivudine- (3TC)-resistant mutants, several other nucleosides with a dioxolane moiety have been synthesized in our laboratories, their anti-HIV activity against drug-sensitive and drug-resistant mutants determined, and their molecular mechanisms studied by molecular modeling.

Results:  Among the series of dioxolane nucleosides, the thymidine (DOT) showed significant and interesting anti-HIV activity against nucleoside-resistant mutants, as shown below. It was found from the molecular modeling studies that the dioxolane moiety plays a significant role in stabilizing the binding between the mutant HIV reverse transcriptase and the nucleoside triphosphate. The anti-HIV activity against NRTI-resistant HIV strains are shown:

Conclusions:  DOT is significantly active against all the nucleoside-resistant HIV-1 mutants. Thus, additional biological studies are warranted to determine the full potential of DOT as a potential clinical candidate.

Keywords: Dioxolane Thymine; HIV-RT mutant resistant; Molecular Modeling