title: 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.
authors: Brown University, Department of Chemistry, Providence, RI 02912, United States.
authors: Dongyuan
authors: D
authors: Piao
authors: Aravind
authors: A
authors: Basavapathruni
authors: Pinar
authors: P
authors: Iyidogan
authors: Guangxiu
authors: G
authors: Dai
authors: Wolfgang
authors: W
authors: Hinz
authors: Adrian S
authors: AS
authors: Ray
authors: Eisuke
authors: E
authors: Murakami
authors: Joy Y
authors: JY
authors: Feng
authors: Fei
authors: F
authors: You
authors: Ginger E
authors: GE
authors: Dutschman
authors: David J
authors: DJ
authors: Austin
authors: Kathlyn A
authors: KA
authors: Parker
authors: Karen S
authors: KS
authors: Anderson
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D015658:HIV Infections / Q000188:drug therapy; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D008958:Models, Molecular; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D011092:Polyethylene Glycols; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
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