title: Mechanism of multivalent nanoparticle encounter with HIV-1 for potency enhancement of peptide triazole virus inactivation.
abstract: Entry of HIV-1 into host cells remains a compelling yet elusive target for developing agents to prevent infection. A peptide triazole (PT) class of entry inhibitor has previously been shown to bind to HIV-1 gp120, suppress interactions of the Env protein at host cell receptor binding sites, inhibit cell infection, and cause envelope spike protein breakdown, including gp120 shedding and, for some variants, virus membrane lysis. We found that gold nanoparticle-conjugated forms of peptide triazoles (AuNP-PT) exhibit substantially more potent antiviral effects against HIV-1 than corresponding peptide triazoles alone. Here, we sought to reveal the mechanism of potency enhancement underlying nanoparticle conjugate function. We found that altering the physical properties of the nanoparticle conjugate, by increasing the AuNP diameter and/or the density of PT conjugated on the AuNP surface, enhanced potency of infection inhibition to impressive picomolar levels. Further, compared with unconjugated PT, AuNP-PT was less susceptible to reduction of antiviral potency when the density of PT-competent Env spikes on the virus was reduced by incorporating a peptide-resistant mutant gp120. We conclude that potency enhancement of virolytic activity and corresponding irreversible HIV-1 inactivation of PTs upon AuNP conjugation derives from multivalent contact between the nanoconjugates and metastable Env spikes on the HIV-1 virus. The findings reveal that multispike engagement can exploit the metastability built into virus the envelope to irreversibly inactivate HIV-1 and provide a conceptual platform to design nanoparticle-based antiviral agents for HIV-1 specifically and putatively for metastable enveloped viruses generally.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, the School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, Pennsylvania 19104.
authors.forename: Arangassery
authors.initials: A
authors.lastname: Rosemary Bastian
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, the School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, Pennsylvania 19104.
authors.forename: Aakansha
authors.initials: A
authors.lastname: Nangarlia
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102.
authors.forename: Lauren D
authors.initials: LD
authors.lastname: Bailey
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102.
authors.forename: Andrew
authors.initials: A
authors.lastname: Holmes
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, the School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, Pennsylvania 19104.
authors.forename: R Venkat
authors.initials: RV
authors.lastname: Kalyana Sundaram
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, the School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, Pennsylvania 19104.
authors.forename: Charles
authors.initials: C
authors.lastname: Ang
authors.affiliation: the Fundação Oswaldo Cruz, Centro de Pesquisas Goncalo Moniz, Salvador-BA 40296-710, Brazil.
authors.forename: Diogo R M
authors.initials: DR
authors.lastname: Moreira
authors.affiliation: the Department of Chemical and Biological Engineering, Drexel University, Philadelphia, Pennsylvania 19104, and.
authors.forename: Kevin
authors.initials: K
authors.lastname: Freedman
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Duffy
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102.
authors.forename: Mark
authors.initials: M
authors.lastname: Contarino
authors.affiliation: the Department of Chemical and Biological Engineering, Drexel University, Philadelphia, Pennsylvania 19104, and.
authors.forename: Cameron
authors.initials: C
authors.lastname: Abrams
authors.affiliation: the Department of Biochemistry and Molecular Biology, Jefferson University, Philadelphia, Pennsylvania 19107.
authors.forename: Michael
authors.initials: M
authors.lastname: Root
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, Irwin.chaiken@drexelmed.edu.
authors.forename: Irwin
authors.initials: I
authors.lastname: Chaiken
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006046:Gold / Q000737:chemistry; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D058726:Nanoconjugates / Q000633:toxicity* / Q000648:ultrastructure; D010316:Particle Size; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding; D014230:Triazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D038301:Virus Inactivation / Q000187:drug effects; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D015699:HIV Envelope Protein gp120; D058726:Nanoconjugates; D010455:Peptides; D014230:Triazoles; D006046:Gold
keywords: Drug Design; Gold Nanoparticles; Human Immunodeficiency Virus (HIV); Microbicide; Nanotechnology; Peptides; Virology; Virolysis; p24 Release