The role of 2',3'-unsaturation on the antiviral activity of anti-HIV nucleosides against 3TC-resistant mutant (M184V)

Bioorg Med Chem Lett. 2003 Jun 16;13(12):1993-6. doi: 10.1016/s0960-894x(03)00330-5.

Abstract

Molecular modeling studies show that the 2',3'-double bond of the sugar moiety of various 2',3'-unsaturated nucleosides interacts with the aromatic moiety of Tyr115 of HIV-1 reverse transcriptase (RT) by hydrophobic pi-pi interaction. In 3TC-resistant mutant (M184V) RT, 2'-fluoro-2',3'-unsaturated nucleosides with a bulky 4'-substituent experience significant steric hindrance with the side chain of Val184.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Substitution
  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacology*
  • Drug Resistance, Viral
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / chemistry
  • HIV Reverse Transcriptase / genetics
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • HIV-1 / genetics
  • Lamivudine / pharmacology
  • Models, Molecular
  • Molecular Conformation
  • Mutation
  • Nucleosides / chemistry*
  • Nucleosides / metabolism
  • Nucleosides / pharmacology*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Tyrosine / chemistry
  • Tyrosine / metabolism

Substances

  • Anti-HIV Agents
  • Nucleosides
  • Reverse Transcriptase Inhibitors
  • Lamivudine
  • Tyrosine
  • HIV Reverse Transcriptase