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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March 2018
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The human immunodeficiency virus. In this issue of the Biochemical Journal, Parajuli et al. report that restricted the HIV Env (envelope glycoprotein) glycan engagement by a lectin reengineered DAVEI protein chimera is sufficient for virolysis. For details, see pages 931–957.
Research Article|
March 09 2018
Restricted HIV-1 Env glycan engagement by lectin-reengineered DAVEI protein chimera is sufficient for lytic inactivation of the virus
Bibek Parajuli;
Bibek Parajuli
1Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, U.S.A.
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Kriti Acharya;
Kriti Acharya
1Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, U.S.A.
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Harry C. Bach;
Harry C. Bach
1Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, U.S.A.
2Department of Biomedical Engineering, Drexel University, Philadelphia, PA 19102, U.S.A.
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Bijay Parajuli;
Bijay Parajuli
1Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, U.S.A.
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Shiyu Zhang;
Shiyu Zhang
2Department of Biomedical Engineering, Drexel University, Philadelphia, PA 19102, U.S.A.
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Amos B. Smith, III;
Amos B. Smith, III
3Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
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Cameron F. Abrams;
Cameron F. Abrams
1Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, U.S.A.
4Department of Chemical and Biological Engineering, Drexel University, Philadelphia, PA 19104, U.S.A.
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Irwin Chaiken
1Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, U.S.A.
Correspondence: Irwin Chaiken (imc23@drexel.edu)
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Publisher: Portland Press Ltd
Received:
August 27 2017
Revision Received:
December 28 2017
Accepted:
January 17 2018
Accepted Manuscript online:
January 17 2018
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2018
Biochem J (2018) 475 (5): 931–957.
Article history
Received:
August 27 2017
Revision Received:
December 28 2017
Accepted:
January 17 2018
Accepted Manuscript online:
January 17 2018
Citation
Bibek Parajuli, Kriti Acharya, Harry C. Bach, Bijay Parajuli, Shiyu Zhang, Amos B. Smith, Cameron F. Abrams, Irwin Chaiken; Restricted HIV-1 Env glycan engagement by lectin-reengineered DAVEI protein chimera is sufficient for lytic inactivation of the virus. Biochem J 15 March 2018; 475 (5): 931–957. doi: https://doi.org/10.1042/BCJ20170662
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