Development of new antiatherosclerotic and antithrombotic drugs utilizing F11 receptor (F11R/JAM-A) peptides

Authors

  • A. Babinska,

    Corresponding author
    1. Division of Nephrology, Department of Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY
    2. Department of Cell Biology and Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY
    • Correspondence to: Dr. Anna Babinska, SUNY Downstate Medical Center, Medicine 450 Clarkson Av, Box#52, Brooklyn, New York; e-mail: ababinska@downstate.edu

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  • C. C. Clement,

    1. Department of Chemistry, Lehman College of the City University of New York Bronx, NY
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  • M. Swiatkowska,

    1. Department of Molecular and Medical Biophysics, Medical University of Lodz, Lodz, Poland
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  • J. Szymanski,

    1. Department of Molecular and Medical Biophysics, Medical University of Lodz, Lodz, Poland
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  • A. Shon,

    1. Division of Nephrology, Department of Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY
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  • Y. H. Ehrlich,

    1. Program in Neuroscience, College of Staten Island of the City University of New York, Staten Island, NY
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  • E. Kornecki,

    1. Division of Nephrology, Department of Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY
    2. Department of Cell Biology and Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY
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  • M. O. Salifu

    1. Division of Nephrology, Department of Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY
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  • This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

ABSTRACT

Peptides with enhanced resistance to proteolysis, based on the amino acid sequence of the F11 receptor molecule (F11R, aka JAM-A/Junctional adhesion molecule-A), were designed, prepared, and examined as potential candidates for the development of anti-atherosclerotic and anti-thrombotic therapeutic drugs. A sequence at the N-terminal of F11R together with another sequence located in the first Ig-loop of this protein, were identified to form a steric active-site operating in the F11R-dependent adhesion between cells that express F11R molecules on their external surface. In silico modeling of the complex between two polypeptide chains with the sequences positioned in the active-site was used to generate peptide-candidates designed to inhibit homophilic interactions between surface-located F11R molecules. The two lead F11R peptides were modified with D-Arg and D-Lys at selective sites, for attaining higher stability to proteolysis in vivo. Using molecular docking experiments we tested different conformational states and the putative binding affinity between two selected D-Arg and D-Lys-modified F11R peptides and the proposed binding pocket. The inhibitory effects of the F11R peptide 2HN-(dK)-SVT-(dR)-EDTGTYTC-CONH2 on antibody-induced platelet aggregation and on the adhesion of platelets to cytokine-inflammed endothelial cells are reported in detail, and the results point out the significant potential utilization of F11R peptides for the prevention and treatment of atherosclerotic plaques and associated thrombotic events. © 2014 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 102: 322–334, 2014.

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