The anti-HIV activity of ADS-J1 targets the HIV-1 gp120.
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.
Armand-Ugón
Mercedes
M
Retrovirology Laboratory IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autónoma de Barcelona, 08916 Barcelona, Spain.
Clotet-Codina
Imma
I
Tintori
Cristina
C
Manetti
Fabrizio
F
Clotet
Bonaventura
B
Botta
Maurizio
M
Esté
José A
JA
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000235:genetics; D000077560:Enfuvirtide; D016655:HIV Core Protein p24 / Q000032:analysis; D015699:HIV Envelope Protein gp120 / Q000187:drug effects* / Q000235:genetics; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D009282:Naphthalenesulfonates / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D000071228:Polyelectrolytes; D011108:Polymers / Q000494:pharmacology; D011485:Protein Binding; D013601:T-Lymphocytes / Q000821:virology; D014227:Triazines / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D000077560:Enfuvirtide; D016655:HIV Core Protein p24; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D009282:Naphthalenesulfonates; D010446:Peptide Fragments; D000071228:Polyelectrolytes; D011108:Polymers; D014227:Triazines; C407149:peptide C34; C407145:ADS J1