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A recombinant allosteric lectin antagonist of HIV-1 envelope gp120 interactions
Journal article   Peer reviewed

A recombinant allosteric lectin antagonist of HIV-1 envelope gp120 interactions

Karyn McFadden, Simon Cocklin, Hosahudya Gopi, Sabine Baxter, Sandya Ajith, Naheed Mahmood, Robin Shattock and Irwin Chaiken
Proteins, structure, function, and bioinformatics, v 67(3), pp 617-629
15 May 2007
DOI: https://doi.org/10.1002/prot.21295
PMID: 17348010
Featured in Collection :   UN Sustainable Development Goals @ Drexel

Abstract

HIV Envelope Protein gp120 - genetics Cricetulus Recombinant Fusion Proteins - pharmacology Bacterial Proteins - chemistry Peptides - genetics HIV Envelope Protein gp120 - metabolism Recombinant Fusion Proteins - metabolism Peptides - metabolism Protein Binding - drug effects Carrier Proteins - chemistry HIV Envelope Protein gp120 - chemistry Lectins - chemistry CHO Cells HIV-1 - metabolism Cricetinae Enzyme-Linked Immunosorbent Assay Peptides - chemistry Electrophoresis, Polyacrylamide Gel Lectins - antagonists & inhibitors Bacterial Proteins - genetics Cells, Cultured Recombinant Fusion Proteins - chemistry Carrier Proteins - genetics Animals Carrier Proteins - metabolism Bacterial Proteins - metabolism CD4 Antigens - metabolism
The first, critical stage of HIV-1 infection is fusion of viral and host cellular membranes initiated by a viral envelope glycoprotein gp120. We evaluated the potential to form a chimeric protein entry inhibitor that combines the action of two gp120-targeting molecules, an allosteric peptide inhibitor 12p1 and a higher affinity carbohydrate-binding protein cyanovirin (CVN). In initial mixing experiments, we demonstrated that the inhibitors do not interfere with each other and instead show functional synergy in inhibiting viral cell infection. Based on this, we created a chimera, termed L5, with 12p1 fused to the C-terminal domain of CVN through a linker of five penta-peptide repeats. L5 revealed the same broad specificity as CVN for gp120 from a variety of clades and tropisms. By comparison to CVN, the L5 chimera exhibited substantially increased inhibition of gp120 binding to receptor CD4, coreceptor surrogate mAb 17b and gp120 antibody F105. These binding inhibition effects by the chimera reflected both the high affinity of the CVN domain and the allosteric action of the 12p1 domain. The results open up the possibility to form high potency chimeras, as well as noncovalent mixtures, as leads for HIV-1 envelope antagonism that can overcome potency limits and potential virus mutational resistance for either 12p1 or CVN alone.

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19 citations in Web of Science
20 citations in Scopus

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