title: A novel cyclic pentapeptide inhibits alpha 4 beta 1 and alpha 5 beta 1 integrin-mediated cell adhesion.
abstract: Lymphocytes and monocytes initiate and modulate inflammatory and immune responses for host defense. This process is dependent upon extravasation of leukocytes from the circulation to sites of antigenic challenge and is controlled, in part, by various integrins, including alpha 4 beta 1 and alpha 5 beta 1. A small cyclic pentapeptide that inhibits, in vitro, both alpha 4 beta 1 and alpha 5 beta 1 activity is described. This peptide, Arg-Cys-Asp-Thioproline-Cys (RC*D[ThioP]C*), is cyclized by a disulfide bond through the cysteine residues (the asterisks denote cyclizing residues). RC*D(ThioP)C* inhibits alpha 5 beta 1-mediated leukocyte adhesion to the 120-kDa Arg-Gly-Asp (RGD)-containing binding site of fibronectin. Two different adhesion activities of alpha 4 beta 1 are also inhibited: alpha 4 beta 1-mediated cell adhesion to the alternatively spliced CS-1 site of fibronectin and the alpha 4 beta 1-dependent binding of leukocytes to cytokine-activated endothelial cells. Both alpha 4 beta 1 and alpha 5 beta 1 can be purified by affinity chromatography using the immobilized pentapeptide. The peptide does not inhibit adhesion to other extracellular matrix proteins including laminin and vitronectin. The specificity of the RC*D(ThioP)C* peptide for alpha 4 beta 1 and alpha 5 beta 1 suggests potential therapeutic utility for inhibiting inflammatory disease.
authors.affiliation: Tanabe Research Laboratories, San Diego, California 92121.
authors.forename: D M
authors.initials: DM
authors.lastname: Nowlin
authors.forename: F
authors.initials: F
authors.lastname: Gorcsan
authors.forename: M
authors.initials: M
authors.lastname: Moscinski
authors.forename: S L
authors.initials: SL
authors.lastname: Chiang
authors.forename: T J
authors.initials: TJ
authors.lastname: Lobl
authors.forename: P M
authors.initials: PM
authors.lastname: Cardarelli
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal; D002448:Cell Adhesion / Q000187:drug effects*; D002478:Cells, Cultured; D002846:Chromatography, Affinity; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D005353:Fibronectins / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000378:metabolism* / Q000502:physiology*; D007700:Kinetics; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000302:isolation & purification / Q000378:metabolism; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding; D017469:Receptors, Fibronectin; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D005353:Fibronectins; D039041:Integrin alpha4beta1; D016023:Integrins; D009363:Neoplasm Proteins; D009842:Oligopeptides; D010456:Peptides, Cyclic; D017469:Receptors, Fibronectin