Journal article
Restricted HIV-1 Env glycan engagement by lectin-reengineered DAVEI protein chimera is sufficient for lytic inactivation of the virus
Biochemical journal, v 475(5), pp 931-957
09 Mar 2018
PMID: 29343613
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
We previously reported a first-generation recombinant DAVEI construct, a dual action virus entry inhibitor composed of cyanovirin-N (CVN) fused to a membrane proximal external region or its derivative peptide Trp3. DAVEI exhibits potent and irreversible inactivation of HIV-1 (human immunodeficiency virus) viruses by dual engagement of gp120 and gp41. However, the promiscuity of CVN to associate with multiple glycosylation sites in gp120 and its multivalency limit current understanding of the molecular arrangement of the DAVEI molecules on trimeric spike. Here, we constructed and investigated the virolytic function of second-generation DAVEI molecules using a simpler lectin, microvirin (MVN). MVN is a monovalent lectin with a single glycan-binding site in gp120, is structurally similar to CVN and exhibits no toxicity or mitogenicity, both of which are liabilities with CVN. We found that, like CVN-DAVEI-L2-3Trp (peptide sequence DKWASLWNW), MVN-DAVEI2-3Trp exploits a similar mechanism of action for inducing HIV-1 lytic inactivation, but by more selective gp120 glycan engagement. By sequence redesign, we significantly increased the potency of MVN-DAVEI2-3Trp protein. Unlike CVN-DAVEI2-3Trp, re-engineered MVN-DAVEI2-3Trp(Q81K/M83R) virolytic activity and its interaction with gp120 were both competed by 2G12 antibody. That the lectin domain in DAVEIs can utilize MVN without loss of virolytic function argues that restricted HIV-1 Env (envelope glycoprotein) glycan engagement is sufficient for virolysis. It also shows that DAVEI lectin multivalent binding with gp120 is not required for virolysis. MVN-DAVEI2-3Trp(Q81K/M83R) provides an improved tool to elucidate productive molecular arrangements of Env-DAVEI enabling virolysis and also opens the way to form DAVEI fusions made up of gp120-binding small molecules linked to Trp3 peptide.
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Details
- Title
- Restricted HIV-1 Env glycan engagement by lectin-reengineered DAVEI protein chimera is sufficient for lytic inactivation of the virus
- Creators
- Bibek Parajuli - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, U.S.AKriti Acharya - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, U.S.AHarry C Bach - Department of Biomedical Engineering, Drexel University, Philadelphia, PA 19102, U.S.ABijay Parajuli - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, U.S.AShiyu Zhang - Department of Biomedical Engineering, Drexel University, Philadelphia, PA 19102, U.S.AAmos B Smith, 3rd - Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, U.S.ACameron F Abrams - Department of Chemical and Biological Engineering, Drexel University, Philadelphia, PA 19104, U.S.AIrwin Chaiken - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, U.S.A. imc23@drexel.edu
- Publication Details
- Biochemical journal, v 475(5), pp 931-957
- Publisher
- England
- Grant note
- P01 GM056550 / NIGMS NIH HHS R01 GM115249 / NIGMS NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; Chemical and Biological Engineering
- Web of Science ID
- WOS:000428087500008
- Scopus ID
- 2-s2.0-85046849456
- Other Identifier
- 991014969860204721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology