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A recombinant allosteric lectin antagonist of HIV‐1 envelope gp120 interactions
Author(s) -
McFadden Karyn,
Cocklin Simon,
Gopi Hosahudya,
Baxter Sabine,
Ajith Sandya,
Mahmood Naheed,
Shattock Robin,
Chaiken Irwin
Publication year - 2007
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.21295
Subject(s) - allosteric regulation , chimera (genetics) , viral envelope , biology , entry inhibitor , lectin , fusion protein , glycoprotein , peptide , viral entry , microbiology and biotechnology , enfuvirtide , recombinant dna , receptor , biochemistry , virology , virus , viral replication , antibody , gene , epitope , gp41 , genetics
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. Proteins 2007. © 2007 Wiley‐Liss, Inc.