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

Bioorg Med Chem Lett. 2013 Mar 1;23(5):1511-8. doi: 10.1016/j.bmcl.2012.12.015. Epub 2012 Dec 20.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Binding Sites
  • Drug Design
  • HIV Infections / drug therapy
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / chemistry
  • HIV-1 / enzymology*
  • Humans
  • Models, Molecular
  • Nucleosides / chemistry
  • Nucleosides / pharmacology
  • Polyethylene Glycols / chemistry
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / metabolism
  • Reverse Transcriptase Inhibitors / pharmacology*

Substances

  • Nucleosides
  • Reverse Transcriptase Inhibitors
  • Polyethylene Glycols
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase