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Bifunctional inhibition of HIV-1 reverse transcriptase: a first step in designing a bifunctional triphosphate.

ABSTRACT: The onset of resistance to approved anti-AIDS drugs by HIV necessitates the search for novel inhibitors of HIV-1 reverse transcriptase (RT). Developing single molecular agents concurrently occupying the nucleoside and nonnucleoside binding sites in RT is an intriguing idea but the proof of concept has so far been elusive. As a first step, we describe molecular modeling to guide focused chemical syntheses of conjugates having nucleoside (d4T) and nonnucleoside (TIBO) moieties tethered by a flexible polyethylene glycol (PEG) linker. A triphosphate of d4T-6PEG-TIBO conjugate was successfully synthesized that is recognized as a substrate by HIV-1 RT and incorporated into a double-stranded DNA.

SUBMITTER: Piao D

PROVIDER: S-EPMC3580853 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Bifunctional inhibition of HIV-1 reverse transcriptase: a first step in designing a bifunctional triphosphate.

Piao Dongyuan D Basavapathruni Aravind A Iyidogan Pinar P Dai Guangxiu G Hinz Wolfgang W Ray Adrian S AS Murakami Eisuke E Feng Joy Y JY You Fei F Dutschman Ginger E GE Austin David J DJ Parker Kathlyn A KA Anderson Karen S KS

Bioorganic & medicinal chemistry letters 20121220 5

The onset of resistance to approved anti-AIDS drugs by HIV necessitates the search for novel inhibitors of HIV-1 reverse transcriptase (RT). Developing single molecular agents concurrently occupying the nucleoside and nonnucleoside binding sites in RT is an intriguing idea but the proof of concept has so far been elusive. As a first step, we describe molecular modeling to guide focused chemical syntheses of conjugates having nucleoside (d4T) and nonnucleoside (TIBO) moieties tethered by a flexib ...[more]

PMID: 23380374

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