title: Template assembled cyclopeptides as multimeric system for integrin targeting and endocytosis.
abstract: The alpha(V)beta(3) integrin receptor plays an important role in human metastasis and tumor-induced angiogenesis. c[-RGDfV-] peptide represents a selective alpha(V)beta(3) integrin ligand that has been extensively used for research, therapy, and diagnosis of neoangiogenesis. We report here the modular synthesis and biological characterization of template assembled cyclopeptides as a multimeric system for targeting and endocytosis of cells expressing alpha(V)beta(3) integrin. c[-RGDfK-] was cleanly assembled in a multivalent mode by chemoselective oxime bond formation to a cyclodecapeptides template labeled by different reporter groups. Binding propensity to the alpha(V)beta(3) receptor and the associated good uptake property displayed by the multivalent molecules demonstrated the interest in the RAFT molecule to design new multimeric system with hitherto unreported properties. These compounds offer an interesting perspective for the reevaluation of integrins as angiogenesis regulators (Hynes, R. O. Nature Med. 2003, 9, 918-921) as well as for the design of more sophisticated systems such as molecular conjugate vectors.
authors.affiliation: LEDSS, UMR CNRS 5616 and ICMG, FR-2607, Université Joseph Fourier, BP 53, 38041 Grenoble Cedex 9, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Boturyn
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Coll
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Garanger
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Favrot
authors.forename: Pascal
authors.initials: P
authors.lastname: Dumy
mesh_terms: D000818:Animals; D016466:CHO Cells; D002448:Cell Adhesion; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D003500:Cyclization; D004705:Endocytosis; D005353:Fibronectins / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D008024:Ligands; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D005353:Fibronectins; D016023:Integrins; D008024:Ligands; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid