title: Development of new antiatherosclerotic and antithrombotic drugs utilizing F11 receptor (F11R/JAM-A) peptides.
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.
authors.affiliation: Division of Nephrology, Department of Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, 11203; Department of Cell Biology and Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, 11203.
authors.forename: A
authors.initials: A
authors.lastname: Babinska
authors.forename: C C
authors.initials: CC
authors.lastname: Clement
authors.forename: M
authors.initials: M
authors.lastname: Swiatkowska
authors.forename: J
authors.initials: J
authors.lastname: Szymanski
authors.forename: A
authors.initials: A
authors.lastname: Shon
authors.forename: Y H
authors.initials: YH
authors.lastname: Ehrlich
authors.forename: E
authors.initials: E
authors.lastname: Kornecki
authors.forename: M O
authors.initials: MO
authors.lastname: Salifu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy*; D001665:Binding Sites; D016207:Cytokines / Q000378:metabolism; D015195:Drug Design; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D062745:Junctional Adhesion Molecule A / Q000737:chemistry*; D051379:Mice; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D016207:Cytokines; D005343:Fibrinolytic Agents; D062745:Junctional Adhesion Molecule A; D010455:Peptides; D011994:Recombinant Proteins
keywords: F11 receptor; F11R/JAMA; anti-atherosclerotic drug; antithrombotic drug; peptide 4D