title: Peptide Triazole Inactivators of HIV-1 Utilize a Conserved Two-Cavity Binding Site at the Junction of the Inner and Outer Domains of Env gp120.
abstract: We used coordinated mutagenesis, synthetic design, and flexible docking to investigate the structural mechanism of Env gp120 encounter by peptide triazole (PT) inactivators of HIV-1. Prior results demonstrated that the PT class of inhibitors suppresses binding at both CD4 and coreceptor sites on Env and triggers gp120 shedding, leading to cell-independent irreversible virus inactivation. Despite these enticing anti-HIV-1 phenotypes, structural understanding of the PT-gp120 binding mechanism has been incomplete. Here we found that PT engages two inhibitor ring moieties at the junction between the inner and outer domains of the gp120 protein. The results demonstrate how combined occupancy of two gp120 cavities can coordinately suppress both receptor and coreceptor binding and conformationally entrap the protein in a destabilized state. The two-cavity model has common features with small molecule gp120 inhibitor binding sites and provides a guide for further design of peptidomimetic HIV-1 inactivators based on the PT pharmacophore.
authors: †Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, United States.
authors: Rachna
authors: R
authors: Aneja
authors: †Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, United States.
authors: Adel A
authors: AA
authors: Rashad
authors: †Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, United States.
authors: Huiyuan
authors: H
authors: Li
authors: †Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, United States.|‡School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, Pennsylvania 19104, United States.
authors: Ramalingam Venkat
authors: RV
authors: Kalyana Sundaram
authors: †Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, United States.
authors: Caitlin
authors: C
authors: Duffy
authors: †Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, United States.
authors: Lauren D
authors: LD
authors: Bailey
authors: †Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, United States.
authors: Irwin
authors: I
authors: Chaiken
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000737:chemistry; D001665:Binding Sites; D015704:CD4 Antigens / Q000737:chemistry; D015699:HIV Envelope Protein gp120 / Q000737:chemistry*; D015497:HIV-1 / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics; D057927:Hydrophobic and Hydrophilic Interactions; D062105:Molecular Docking Simulation; D009154:Mutation; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D057786:Peptidomimetics / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology; D038301:Virus Inactivation
chemical_list: D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D010455:Peptides; D057786:Peptidomimetics; D014230:Triazoles