title: Structure-activity relationship studies of indole-based compounds as small molecule HIV-1 fusion inhibitors targeting glycoprotein 41.
abstract: We previously described indole-containing compounds with the potential to inhibit HIV-1 fusion by targeting the hydrophobic pocket of transmembrane glycoprotein gp41. Here we report optimization and structure-activity relationship studies on the basic scaffold, defining the role of shape, contact surface area, and molecular properties. Thirty new compounds were evaluated in binding, cell-cell fusion, and viral replication assays. Below a 1 μM threshold, correlation between binding and biological activity was diminished, indicating an amphipathic requirement for activity in cells. The most active inhibitor 6j exhibited 0.6 μM binding affinity and 0.2 μM EC50 against cell-cell fusion and live virus replication and was active against T20 resistant strains. Twenty-two compounds with the same connectivity displayed a consensus pose in docking calculations, with rank order matching the biological activity. The work provides insight into requirements for small molecule inhibition of HIV-1 fusion and demonstrates a potent low molecular weight fusion inhibitor.
authors.affiliation: Department of Basic Sciences, Touro University-California , 1310 Club Drive, Mare Island, Vallejo, California 94592, United States.
authors.forename: Guangyan
authors.initials: G
authors.lastname: Zhou
authors.forename: Vladimir
authors.initials: V
authors.lastname: Sofiyev
authors.forename: Hardeep
authors.initials: H
authors.lastname: Kaur
authors.forename: Beth A
authors.initials: BA
authors.lastname: Snyder
authors.forename: Marie K
authors.initials: MK
authors.lastname: Mankowski
authors.forename: Priscilla A
authors.initials: PA
authors.lastname: Hogan
authors.forename: Roger G
authors.initials: RG
authors.lastname: Ptak
authors.forename: Miriam
authors.initials: M
authors.lastname: Gochin
mesh_terms: D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002459:Cell Fusion; D002460:Cell Line; D024882:Drug Resistance, Viral; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000378:metabolism* / Q000494:pharmacology; D023581:HIV Fusion Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D062105:Molecular Docking Simulation; D010446:Peptide Fragments / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: C000591349:3-((6-(1-((3-methoxycarbonylphenyl)methyl)indol-6-yl)indol-1-yl)methyl)benzoic acid; D001565:Benzoates; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D007211:Indoles; D010446:Peptide Fragments; D000077560:Enfuvirtide