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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
Journal article   Open access   Peer reviewed

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

Rachna Aneja, Adel A Rashad, Huiyuan Li, Ramalingam Venkat Kalyana Sundaram, Caitlin Duffy, Lauren D Bailey and Irwin Chaiken
Journal of medicinal chemistry, v 58(9), pp 3843-3858
14 May 2015
DOI: https://doi.org/10.1021/acs.jmedchem.5b00073
PMID: 25860784
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://europepmc.org/articles/pmc4497506View
Accepted (AM)Open Access (License Unspecified),  Open

Abstract

Anti-HIV Agents - chemistry Anti-HIV Agents - pharmacology Antibodies, Monoclonal - chemistry Binding Sites CD4 Antigens - chemistry HIV Envelope Protein gp120 - chemistry HIV-1 - chemistry HIV-1 - drug effects HIV-1 - genetics Hydrophobic and Hydrophilic Interactions Molecular Docking Simulation Mutation Peptides - chemistry Peptides - pharmacology Peptidomimetics - chemistry Peptidomimetics - pharmacology Protein Binding Structure-Activity Relationship Thermodynamics Triazoles - chemistry Triazoles - pharmacology Virus Inactivation
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.

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43 citations in Web of Science
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Web of Science research areas
Chemistry, Medicinal
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