title: β-hairpin peptide that targets vascular endothelial growth factor (VEGF) receptors: design, NMR characterization, and biological activity.
abstract: VEGF receptors have been the target of intense research aimed to develop molecules able to inhibit or stimulate angiogenesis. Based on the x-ray structure of the complex placental growth factor-VEGF receptor 1(D2), we designed a VEGF receptor-binding peptide reproducing the placental growth factor β-hairpin region Gln(87)-Val(100) that is involved in receptor recognition. A conformational analysis showed that the designed peptide adopts the expected fold in pure water. Moreover, a combination of NMR interaction analysis and cell binding studies were used to demonstrate that the peptide targets VEGF receptors. The VEGF receptor 1(D2)-interacting residues were characterized at the molecular level, and they correspond to the residues recognizing the placental growth factor sequence Gln(87)-Val(100). Finally, the peptide biological activity was characterized in vitro and in vivo, and it showed a VEGF-like behavior. Indeed, the peptide activated VEGF-dependent intracellular pathways, induced endothelial cell proliferation and rescue from apoptosis, and promoted angiogenesis in vivo. This compound is one of the few peptides known with proangiogenic activity, which makes it a candidate for the development of a novel peptide-based drug for medical applications in therapeutic angiogenesis.
authors.affiliation: Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche, via Mezzocannone 16, 80134 Napoli, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Diana
authors.affiliation: Dipartimento di Scienze Farmaceutiche e Biomediche, Università di Salerno, via Ponte don Melillo, 84084 Fisciano (Salerno), Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Basile
authors.affiliation: Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche, via Mezzocannone 16, 80134 Napoli, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: De Rosa
authors.affiliation: Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche, via Mezzocannone 16, 80134 Napoli, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Di Stasi
authors.affiliation: Dipartimento delle Scienze Biologiche, Università di Napoli "Federico II," via Mezzocannone 16, 80134 Napoli, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Auriemma
authors.affiliation: Istituto Nazionale Tumori "Fondazione G. Pascale," via Mariano Semmola 49, 80131 Napoli, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Arra
authors.affiliation: Dipartimento delle Scienze Biologiche, Università di Napoli "Federico II," via Mezzocannone 16, 80134 Napoli, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Pedone
authors.affiliation: Dipartimento di Scienze Farmaceutiche e Biomediche, Università di Salerno, via Ponte don Melillo, 84084 Fisciano (Salerno), Italy.
authors.forename: Maria Caterina
authors.initials: MC
authors.lastname: Turco
authors.affiliation: Dipartimento di Scienze Ambientali, Seconda Università di Napoli, via Antonio Vivaldi 43, 81100 Caserta, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Fattorusso
authors.affiliation: Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche, via Mezzocannone 16, 80134 Napoli, Italy. Electronic address: ldandrea@unina.it.
authors.forename: Luca Domenico
authors.initials: LD
authors.lastname: D'Andrea
mesh_terms: D000818:Animals; D006801:Humans; D051379:Mice; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000819:agonists* / Q000378:metabolism
chemical_list: D010455:Peptides; D040281:Vascular Endothelial Growth Factor Receptor-1