title: Recognition of HIV-inactivating peptide triazoles by the recombinant soluble Env trimer, BG505 SOSIP.664.
abstract: Peptide triazole (PT) antagonists interact with gp120 subunits of HIV-1 Env trimers to block host cell receptor interactions, trigger gp120 shedding, irreversibly inactivate virus and inhibit infection. Despite these enticing functions, understanding the structural mechanism of PT-Env trimer encounter has been limited. In this work, we combined competition interaction analysis and computational simulation to demonstrate PT binding to the recombinant soluble trimer, BG505 SOSIP.664, a stable variant that resembles native virus spikes in binding to CD4 receptor as well as known conformationally-dependent Env antibodies. Binding specificity and computational modeling fit with encounter through complementary PT pharmacophore Ile-triazolePro-Trp interaction with a 2-subsite cavity in the Env gp120 subunit of SOSIP trimer similar to that in monomeric gp120. These findings argue that PTs are able to recognize and bind a closed prefusion state of Env trimer upon HIV-1 encounter. The results provide a structural model of how PTs exert their function on virion trimeric spike protein and a platform to inform future antagonist design. Proteins 2017; 85:843-851. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University, Philadelphia, Pennsylvania, 19102.
authors.forename: Kriti
authors.identifier: 0000-0002-3408-149X
authors.initials: K
authors.lastname: Acharya
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University, Philadelphia, Pennsylvania, 19102.
authors.forename: Adel A
authors.initials: AA
authors.lastname: Rashad
authors.affiliation: Department of Chemical and Biological Engineering, Drexel University, Philadelphia, Pennsylvania, 19104.
authors.forename: Francesca
authors.initials: F
authors.lastname: Moraca
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York, 10065.
authors.forename: Per Johan
authors.initials: PJ
authors.lastname: Klasse
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York, 10065.
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
authors.affiliation: Department of Chemical and Biological Engineering, Drexel University, Philadelphia, Pennsylvania, 19104.
authors.forename: Cameron
authors.initials: C
authors.lastname: Abrams
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University, Philadelphia, Pennsylvania, 19102.
authors.forename: Irwin
authors.initials: I
authors.lastname: Chaiken
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000737:chemistry*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry*; D001665:Binding Sites; D001667:Binding, Competitive; D016466:CHO Cells; D003412:Cricetulus; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012995:Solubility; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D000914:Antibodies, Viral; D000998:Antiviral Agents; D015699:HIV Envelope Protein gp120; D010455:Peptides; D011994:Recombinant Proteins; D014230:Triazoles
keywords: Env trimer; HIV-1; SOSIP; peptide triazole; virus inactivation