title: Cyclic RGD peptide inhibits alpha 4 beta 1 interaction with connecting segment 1 and vascular cell adhesion molecule.
abstract: The integrin supergene family includes receptors for a variety of extracellular matrix as well as cell surface proteins. Integrin alpha 4 has been shown to play an important role in leukocyte adhesion and extravasation during immune and inflammatory reactions. One recognition sequence known to interact with alpha 4 is the Leu-Asp-Val (LDV) site contained in the connecting segment 1 region of fibronectin. Here we present evidence that shows that a conformationally restricted RGD-containing peptide is a potent inhibitor of cell adhesion mediated by alpha 4 beta 1, a receptor not convincingly documented to interact with RGD peptides. This peptide, 1-adamantaneacetyl-Cys-Gly-Arg-Gly-Asp-Ser-Pro-Cys (disulfide bridge between residues 1-8), blocks Jurkat cell adhesion to connecting segment 1-containing peptides as well as cell adhesion to cytokine-activated endothelial cells. Adhesion of Jurkat cells to either vascular cell adhesion molecule-expressing cells or recombinant vascular cell adhesion molecule-coated plates was likewise inhibited by this peptide. Furthermore, alpha 4 beta 1 can bind directly to a cyclic RGD peptide immobilized to Sepharose. Integrins, alpha 5 beta 1, alpha v beta 3, alpha IIb/beta IIIa, alpha 2 beta 1, alpha v beta 1, alpha v beta 5, alpha v beta 6, and alpha 3 beta 1, have been shown to recognize the Arg-Gly-Asp (RGD) sequence present in a variety of extracellular matrix proteins, and our data support the addition of alpha 4 beta 1 to this group. Further studies using molecular modeling of such cyclic RGD peptides could help in the design of more potent peptides or nonpeptide mimetics that could effectively block alpha 4-mediated activity and have potential application in a number of inflammatory diseases.
authors.affiliation: Tanabe Research Laboratories, San Diego, California 92121.
authors.forename: P M
authors.initials: PM
authors.lastname: Cardarelli
authors.forename: R R
authors.initials: RR
authors.lastname: Cobb
authors.forename: D M
authors.initials: DM
authors.lastname: Nowlin
authors.forename: W
authors.initials: W
authors.lastname: Scholz
authors.forename: F
authors.initials: F
authors.lastname: Gorcsan
authors.forename: M
authors.initials: M
authors.lastname: Moscinski
authors.forename: M
authors.initials: M
authors.lastname: Yasuhara
authors.forename: S L
authors.initials: SL
authors.lastname: Chiang
authors.forename: T J
authors.initials: TJ
authors.lastname: Lobl
mesh_terms: D000595:Amino Acid Sequence; D000906:Antibodies / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects*; D015815:Cell Adhesion Molecules / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002846:Chromatography, Affinity; D004305:Dose-Response Relationship, Drug; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005353:Fibronectins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors / Q000502:physiology*; D007700:Kinetics; D008969:Molecular Sequence Data; D005810:Multigene Family; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection; D014407:Tumor Cells, Cultured; D019010:Vascular Cell Adhesion Molecule-1
chemical_list: D000906:Antibodies; D015815:Cell Adhesion Molecules; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D039041:Integrin alpha4beta1; D016023:Integrins; D010446:Peptide Fragments; D010455:Peptides; D010456:Peptides, Cyclic; D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1