The anti-HIV activity of ADS-J1 targets the HIV-1 gp120

• Published in: Virology (New York, N.Y.) Vol. 343; no. 1; pp. 141 - 149
• Main Authors: Armand-Ugón, Mercedes, Clotet-Codina, Imma, Tintori, Cristina, Manetti, Fabrizio, Clotet, Bonaventura, Botta, Maurizio, Esté, José A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.12.2005
• Subjects: Amino Acid Sequence; Amino Acid Substitution; Anti-HIV Agents - pharmacology; Cell Line; Drug resistance; Drug Resistance, Viral - genetics; Entry; Fusion; gp120; gp41; HIV Core Protein p24 - analysis; HIV Envelope Protein gp120 - drug effects; HIV Envelope Protein gp120 - genetics; HIV Envelope Protein gp41 - pharmacology; HIV-1; HIV-1 - drug effects; Human immunodeficiency virus 1; Humans; Molecular Sequence Data; Mutation; Mutation, Missense; Naphthalenesulfonates - pharmacology; Peptide Fragments - pharmacology; Polymers - pharmacology; Protein Binding; T-Lymphocytes - virology; Triazines - pharmacology; Virus Replication - drug effects; HIV-1; gp120; Entry; Drug resistance; Fusion; gp41
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1016/j.virol.2005.08.007

Recent data suggest that heparin sulfates may bind to a CD4 induced epitope in the HIV-1 gp120 that constitutes the coreceptor binding site. We have studied the mechanism of action of ADS-J1, a non-peptidic compound selected by docking analysis to interact with gp41 and to interfere with the formation of N-36/C-34 complexes in sandwich ELISA experiments. We show that ADS-J1 blocked the binding of wild-type HIV-1 NL4-3 strain to MT-4 cells but not virus–cell binding of a polyanion-resistant virus. However, ADS-J1 blocked the replication of polyanion-resistant, T-20- and C34-resistant HIV-1, suggesting a second mechanism of action. Development of resistance to ADS-J1 on the polyanion-resistant HIV-1 led to mutations in gp120 coreceptor binding site and not in gp41. Time of addition experiments confirmed that ADS-J1, but not polyanions such as dextran sulfate or AR177, worked at a step that mimics the activity of an HIV coreceptor antagonist but prior to gp41-dependent fusion. We conclude that ADS-J1 may bind to the HIV coreceptor binding site as its mechanism of anti-HIV activity.