Extension of the Polyanionic Cosalane Pharmacophore as a Strategy for Increasing Anti-HIV Potency

• Published in: Journal of medicinal chemistry Vol. 42; no. 10; pp. 1767 - 1777
• Main Authors: Cushman, Mark, Insaf, Shabana, Paul, Gitendra, Ruell, Jeffrey A, De Clercq, Erik, Schols, Dominique, Pannecouque, Christophe, Witvrouw, Myriam, Schaeffer, Catherine A, Turpin, Jim A, Williamson, Karen, Rice, William G
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 20-05-1999
• Subjects: AIDS/HIV; Animals; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - metabolism; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Aurintricarboxylic Acid - analogs & derivatives; Aurintricarboxylic Acid - chemistry; Benzoates - chemical synthesis; Benzoates - chemistry; Benzoates - metabolism; Benzoates - pharmacology; Biological and medical sciences; 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; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Protein Binding; Structure-Activity Relationship; Steroid; Polyanion; Benzene derivatives; Retroviridae; Haloether; Lentivirus; In vitro; Modeling; Virus; Sodium Compounds; Organic anion; Biological fixation; Position isomer; Structure activity relation; Carboxylic acid; Chlorine Organic compounds; T-Lymphocyte; Molecular model; Organic salt; Carboxylate; Antiviral; Human immunodeficiency virus; Mechanism of action; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980727m

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.