title: Disulfide Sensitivity in the Env Protein Underlies Lytic Inactivation of HIV-1 by Peptide Triazole Thiols.
abstract: We investigated the mode of action underlying lytic inactivation of HIV-1 virions by peptide triazole thiol (PTT), in particular the relationship between gp120 disulfides and the C-terminal cysteine-SH required for virolysis. Obligate PTT dimer obtained by PTT SH cross-linking and PTTs with serially truncated linkers between pharmacophore isoleucine-ferrocenyltriazole-proline-tryptophan and cysteine-SH were synthesized. PTT variants showed loss of lytic activity but not binding and infection inhibition upon SH blockade. A disproportionate loss of lysis activity vs binding and infection inhibition was observed upon linker truncation. Molecular docking of PTT onto gp120 argued that, with sufficient linker length, the peptide SH could approach and disrupt several alternative gp120 disulfides. Inhibition of lysis by gp120 mAb 2G12, which binds at the base of the V3 loop, as well as disulfide mutational effects, argued that PTT-induced disruption of the gp120 disulfide cluster at the base of the V3 loop is an important step in lytic inactivation of HIV-1. Further, PTT-induced lysis was enhanced after treating virus with reducing agents dithiothreitol and tris (2-carboxyethyl)phosphine. Overall, the results are consistent with the view that the binding of PTT positions the peptide SH group to interfere with conserved disulfides clustered proximal to the CD4 binding site in gp120, leading to disulfide exchange in gp120 and possibly gp41, rearrangement of the Env spike, and ultimately disruption of the viral membrane. The dependence of lysis activity on thiol-disulfide interaction may be related to intrinsic disulfide exchange susceptibility in gp120 that has been reported previously to play a role in HIV-1 cell infection.
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine , Philadelphia, Pennsylvania 19102, United States.
authors.forename: Lauren D
authors.initials: LD
authors.lastname: Bailey
authors.affiliation: Department of 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.forename: Ramalingam Venkat
authors.initials: RV
authors.lastname: Kalyana Sundaram
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine , Philadelphia, Pennsylvania 19102, United States.
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine , Philadelphia, Pennsylvania 19102, United States.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Duffy
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine , Philadelphia, Pennsylvania 19102, United States.
authors.forename: Rachna
authors.initials: R
authors.lastname: Aneja
authors.affiliation: Department of Biomedical Engineering, Northwestern University , Evanston, Illinois 60208, United States.
authors.forename: Arangassery
authors.initials: A
authors.lastname: Rosemary Bastian
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine , Philadelphia, Pennsylvania 19102, United States.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Holmes
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine , Philadelphia, Pennsylvania 19102, United States.
authors.forename: Kantharaju
authors.initials: K
authors.lastname: Kamanna
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine , Philadelphia, Pennsylvania 19102, United States.
authors.forename: Adel A
authors.initials: AA
authors.lastname: Rashad
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine , Philadelphia, Pennsylvania 19102, United States.
authors.forename: Irwin
authors.initials: I
authors.lastname: Chaiken
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D019281:Dimerization; D004220:Disulfides / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D008954:Models, Biological; D062105:Molecular Docking Simulation; D009154:Mutation; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000494:pharmacology*; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology; D038301:Virus Inactivation
chemical_list: D000998:Antiviral Agents; D004220:Disulfides; D015699:HIV Envelope Protein gp120; D010455:Peptides; D013438:Sulfhydryl Compounds; D014230:Triazoles