Logo image
Back
HIV-1 Env gp120 structural determinants for peptide triazole dual receptor site antagonism
Journal article   Open access   Peer reviewed

HIV-1 Env gp120 structural determinants for peptide triazole dual receptor site antagonism

Ferit Tuzer, Navid Madani, Kantharaju Kamanna, Isaac Zentner, Judith LaLonde, Andrew Holmes, Elizabeth Upton, Srivats Rajagopal, Karyn McFadden, Mark Contarino, …
Proteins, structure, function, and bioinformatics, v 81(2)
Feb 2013
DOI: https://doi.org/10.1002/prot.24184
PMID: 23011758
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1002/prot.24184View
Published, Version of Record (VoR) Open

Abstract

Anti-HIV Agents - pharmacology HIV Envelope Protein gp120 - genetics Peptides - chemistry Triazoles - chemistry Humans HIV Envelope Protein gp120 - antagonists & inhibitors Models, Molecular Structure-Activity Relationship Mutation - genetics HIV Envelope Protein gp120 - metabolism Triazoles - metabolism Anti-HIV Agents - chemistry Peptides - metabolism CD4 Antigens - chemistry Protein Binding HIV Envelope Protein gp120 - chemistry Kinetics CD4 Antigens - metabolism
Despite advances in HIV therapy, viral resistance and side-effects with current drug regimens require targeting new components of the virus. Dual antagonist peptide triazoles (PT) are a novel class of HIV-1 inhibitors that specifically target the gp120 component of the viral spike and inhibit its interaction with both of its cell surface protein ligands, namely the initial receptor CD4 and the co-receptor (CCR5/CXCR4), thus preventing viral entry. Following an initial survey of 19 gp120 alanine mutants by ELISA, we screened 11 mutants for their importance in binding to, and inhibition by the PT KR21 using surface plasmon resonance. Key mutants were purified and tested for their effects on the peptide's affinity and its ability to inhibit binding of CD4 and the co-receptor surrogate mAb 17b. Effects of the mutations on KR21 viral neutralization were measured by single-round cell infection assays. Two mutations, D474A and T257A, caused large-scale loss of KR21 binding, as well as losses in both CD4/17b and viral inhibition by KR21. A set of other Ala mutants revealed more moderate losses in direct binding affinity and inhibition sensitivity to KR21. The cluster of sensitive residues defines a PT functional epitope. This site is in a conserved region of gp120 that overlaps the CD4 binding site and is distant from the co-receptor/17b binding site, suggesting an allosteric mode of inhibition for the latter. The arrangement and sequence conservation of the residues in the functional epitope explain the breadth of antiviral activity, and improve the potential for rational inhibitor development.

Metrics

9 Record Views
16 citations in Web of Science
15 citations in Scopus

Details

UN Sustainable Development Goals (SDGs)

This publication has contributed to the advancement of the following goals:

#3 Good Health and Well-Being

InCites Highlights

Data related to this publication, from InCites Benchmarking & Analytics tool:

Collaboration types
Industry collaboration
Domestic collaboration
International collaboration
Web of Science research areas
Biochemistry & Molecular Biology
Biophysics
Logo image