Extension of the polyanionic cosalane pharmacophore as a strategy for increasing anti-HIV potency

J Med Chem. 1999 May 20;42(10):1767-77. doi: 10.1021/jm980727m.

Abstract

The anti-HIV agent cosalane inhibits both the binding of gp120 to CD4 as well as an undefined postattachment event prior to reverse transcription. Several cosalane analogues having an extended polyanionic "pharmacophore" were designed based on a hypothetical model of the binding of cosalane to CD4. The analogues were synthesized, and a number of them displayed anti-HIV activity. One of the new analogues was found to possess enhanced potency as an anti-HIV agent relative to cosalane itself. Although the new analogues inhibited both HIV-1 and HIV-2, they were more potent as inhibitors of HIV-1 than HIV-2. Mechanism of action studies indicated that the most potent of the new analogues inhibited fusion of the viral envelope with the cell membrane at lower concentrations than it inhibited attachment, suggesting inhibition of fusion as the primary mechanism of action.

Publication types

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

MeSH terms

  • Animals
  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / metabolism
  • Anti-HIV Agents / pharmacology
  • Aurintricarboxylic Acid / analogs & derivatives*
  • Aurintricarboxylic Acid / chemistry
  • Benzoates / chemical synthesis*
  • Benzoates / chemistry
  • Benzoates / metabolism
  • Benzoates / pharmacology
  • CD4 Antigens / chemistry
  • CD4 Antigens / metabolism
  • Cell Line
  • Cholestanes / chemical synthesis*
  • Cholestanes / chemistry
  • Cholestanes / metabolism
  • Cholestanes / pharmacology
  • HIV-1 / drug effects
  • HIV-2 / drug effects
  • Humans
  • Models, Molecular
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • 3'',3'''-dichloro-4'',4'''-bis(4-carboxybenzyloxy)-5'',5'''-dicarboxy-4',4'-diphenyl-3-(1-(3'-butenyl))cholestane
  • Anti-HIV Agents
  • Benzoates
  • CD4 Antigens
  • Cholestanes
  • cosalane
  • Aurintricarboxylic Acid