title: Extension of the polyanionic cosalane pharmacophore as a strategy for increasing anti-HIV potency.
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.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: M
authors.initials: M
authors.lastname: Cushman
authors.forename: S
authors.initials: S
authors.lastname: Insaf
authors.forename: G
authors.initials: G
authors.lastname: Paul
authors.forename: J A
authors.initials: JA
authors.lastname: Ruell
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: D
authors.initials: D
authors.lastname: Schols
authors.forename: C
authors.initials: C
authors.lastname: Pannecouque
authors.forename: M
authors.initials: M
authors.lastname: Witvrouw
authors.forename: C A
authors.initials: CA
authors.lastname: Schaeffer
authors.forename: J A
authors.initials: JA
authors.lastname: Turpin
authors.forename: K
authors.initials: K
authors.lastname: Williamson
authors.forename: W G
authors.initials: WG
authors.lastname: Rice
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001312:Aurintricarboxylic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015704:CD4 Antigens / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D002776:Cholestanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: C119212:3'',3'''-dichloro-4'',4'''-bis(4-carboxybenzyloxy)-5'',5'''-dicarboxy-4',4'-diphenyl-3-(1-(3'-butenyl))cholestane; D019380:Anti-HIV Agents; D001565:Benzoates; D015704:CD4 Antigens; D002776:Cholestanes; C083060:cosalane; D001312:Aurintricarboxylic Acid