title: Diminished oligomerization in the synthesis of new anti-angiogenic cyclic peptide using solution instead of solid-phase cyclization.
abstract: The design and synthesis of novel peptides that inhibit angiogenesis is an important area for anti-angiogenic drug development. Cyclic and small peptides present several advantages for therapeutic application, including stability, solubility, increased bio-availability and lack of immune response in the host cell. We describe here the synthesis and biological evaluations of a new cyclic peptide analog of CBO-P11: cyclo(RIKPHE), designated herein as CBO-P23M, a hexamer peptide encompassing residues 82 to 86 of VEGF which are involved in the interaction with VEGF receptor-2. CBO-P23M was prepared using in solution cyclization, therefore reducing the peptide cyclodimerization occurred during solid-phase cyclization. The cyclic dimer of CBO-P23M, which was obtained as the main side product during synthesis of the corresponding monomer, was also isolated and investigated. Both peptides markedly reduce VEGF-A-induced phosphorylation of VEGFR-2 and Erk1/2. Moreover, they exhibit anti-angiogenic activity in an in vitro morphogenesis study. Therefore CBO-P23M and CBO-P23M dimer appear as attractive candidates for the development of novel angiogenesis inhibitors for the treatment of cancer and other angiogenesis-related diseases. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 368-375, 2016.
authors.affiliation: ARNA Laboratory, Université de Bordeaux, UFR Des Sciences Pharmaceutiques, Bordeaux Cedex, F-33076, France.|ARNA Laboratory, INSERM U1212, UMR CNRS 5320, 146 Rue Léo Saignat,, Bordeaux Cedex, 33076, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rubio
authors.affiliation: CHU de Poitiers, 2 Rue De La Milétrie, CS90577, Poitiers, 86021, France.|Université de Poitiers, UMR-CNRS 7285, Institut de Chimie des Milieux et des Matériaux de Poitiers, Groupe Systèmes Moléculaires Programmés, 4 Rue Michel Brunet, TSA 51106, Poitiers, 86073, France.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Clarhaut
authors.affiliation: CHU de Poitiers, 2 Rue De La Milétrie, CS90577, Poitiers, 86021, France.|Université de Poitiers, ERL-CNRS 7368, 1 Rue Georges Bonnet, TSA 51106, Poitiers, 86073, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Péraudeau
authors.affiliation: ARNA Laboratory, Université de Bordeaux, UFR Des Sciences Pharmaceutiques, Bordeaux Cedex, F-33076, France.|ARNA Laboratory, INSERM U1212, UMR CNRS 5320, 146 Rue Léo Saignat,, Bordeaux Cedex, 33076, France.|Department of Pharmacy, University of Naples "Federico II," and CIRPeB, via Mezzocannone 16, I-80134, Naples, Italy.
authors.forename: Marian
authors.initials: M
authors.lastname: Vincenzi
authors.affiliation: ARNA Laboratory, Université de Bordeaux, UFR Des Sciences Pharmaceutiques, Bordeaux Cedex, F-33076, France.|ARNA Laboratory, INSERM U1212, UMR CNRS 5320, 146 Rue Léo Saignat,, Bordeaux Cedex, 33076, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Soum
authors.affiliation: Department of Pharmacy, University of Naples "Federico II," and CIRPeB, via Mezzocannone 16, I-80134, Naples, Italy.
authors.forename: Filomena
authors.initials: F
authors.lastname: Rossi
authors.affiliation: ARNA Laboratory, Université de Bordeaux, UFR Des Sciences Pharmaceutiques, Bordeaux Cedex, F-33076, France.|ARNA Laboratory, INSERM U1212, UMR CNRS 5320, 146 Rue Léo Saignat,, Bordeaux Cedex, 33076, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Guillon
authors.affiliation: Université de Poitiers, UMR-CNRS 7285, Institut de Chimie des Milieux et des Matériaux de Poitiers, Groupe Systèmes Moléculaires Programmés, 4 Rue Michel Brunet, TSA 51106, Poitiers, 86073, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Papot
authors.affiliation: ARNA Laboratory, Université de Bordeaux, UFR Des Sciences Pharmaceutiques, Bordeaux Cedex, F-33076, France.|ARNA Laboratory, INSERM U1212, UMR CNRS 5320, 146 Rue Léo Saignat,, Bordeaux Cedex, 33076, France.
authors.forename: Luisa
authors.initials: L
authors.lastname: Ronga
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D003500:Cyclization; D019281:Dimerization; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction; D012996:Solutions / Q000737:chemistry*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D010456:Peptides, Cyclic; D012996:Solutions; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: CBO-P11; CBO-P23M; angiogenesis; cyclic peptide; dimerization; in solution cyclization; solid-supported cyclization