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: Arangassery Rosemary Bastian, Aakansha Nangarlia, Lauren D Bailey, Andrew Holmes, R Venkat Kalyana Sundaram, Charles Ang, Diogo R M Moreira, Kevin Freedman, Caitlin Duffy, Mark Contarino, Cameron Abrams, Michael Root, Irwin Chaiken
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 1 Pg. 529-43 (Jan 02 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 25371202 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Anti-HIV Agents
• HIV Envelope Protein gp120
• Nanoconjugates
• Peptides
• Triazoles
• Gold

Topics

• Anti-HIV Agents (chemical synthesis, pharmacology)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Gold (chemistry)
• HIV Envelope Protein gp120 (antagonists & inhibitors, chemistry)
• HIV-1 (drug effects, growth & development)
• Humans
• Nanoconjugates (toxicity, ultrastructure)
• Particle Size
• Peptides (chemical synthesis, pharmacology)
• Protein Binding
• Triazoles (chemical synthesis, pharmacology)
• Virus Inactivation (drug effects)
• Virus Internalization (drug effects)