title: Disulfide and amide-bridged cyclic peptide analogues of the VEGF₈₁₋₉₁ fragment: synthesis, conformational analysis and biological evaluation.
abstract: The design, synthesis, conformational studies and binding affinity for VEGFR-1 receptors of a collection of linear and cyclic peptide analogues of the β-hairpin fragment VEGF(81-91) are described. Cyclic 11-mer peptide derivatives were prepared from linear precursors with conveniently located Cys, Asp or Dap residues, by the formation of disulfide and amide bridges, using solid-phase synthesis. Molecular modelling studies indicated a tendency to be structured around the central β-turn of the VEGF(81-91) β-hairpin in most synthesized cyclic compounds. This structural behavior was confirmed by NMR conformational analysis. The NHCO cyclic derivative 7 showed significant affinity for VEGFR-1, slightly higher than the native linear fragment, thus supporting the design of mimics of this fragment as a valid approach to disrupt the VEGF/VEGFR-1 interaction.
authors.affiliation: Instituto de Química Médica, IQM-CSIC. C/Juan de Cierva, 3. 28006 Madrid, Spain.
authors.forename: María Isabel
authors.initials: MI
authors.lastname: García-Aranda
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Mirassou
authors.forename: Benoit
authors.initials: B
authors.lastname: Gautier
authors.forename: Mercedes
authors.initials: M
authors.lastname: Martín-Martínez
authors.forename: Nicolas
authors.initials: N
authors.lastname: Inguimbert
authors.forename: Michel
authors.initials: M
authors.lastname: Vidal
authors.forename: María Teresa
authors.initials: MT
authors.lastname: García-López
authors.forename: María Angeles
authors.initials: MA
authors.lastname: Jiménez
authors.forename: Rosario
authors.initials: R
authors.lastname: González-Muñiz
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Pérez de Vega
mesh_terms: D000577:Amides / Q000737:chemistry; D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004220:Disulfides / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D060327:Solid-Phase Synthesis Techniques; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*
chemical_list: D000577:Amides; D020533:Angiogenesis Inhibitors; D004220:Disulfides; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1