title: Combined Use of Oligopeptides, Fragment Libraries, and Natural Compounds: A Comprehensive Approach To Sample the Druggability of Vascular Endothelial Growth Factor.
abstract: The modulation of protein-protein interactions (PPIs) is emerging as a highly promising tool to fight diseases. However, whereas an increasing number of compounds are able to disrupt peptide-mediated PPIs efficiently, the inhibition of domain-domain PPIs appears to be much more challenging. Herein, we report our results related to the interaction between vascular endothelial growth factor (VEGF) and its receptor (VEGFR). The VEGF-VEGFR interaction is a typical domain-domain PPI that is highly relevant for the treatment of cancer and some retinopathies. Our final goal was to identify ligands able to bind VEGF at the region used by the growth factor to interact with its receptor. We undertook an extensive study, combining a variety of experimental approaches, including NMR-spectroscopy-based screening of small organic fragments, peptide libraries, and medicinal plant extracts. The key feature of the successful ligands that emerged from this study was their capacity to expose hydrophobic functional groups able to interact with the hydrophobic hot spots at the interacting VEGF surface patch.
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, 08028, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Bayó-Puxan
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, 08028, Spain.
authors.forename: Ricard
authors.initials: R
authors.lastname: Rodríguez-Mias
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, 08028, Spain.
authors.forename: Michael
authors.initials: M
authors.lastname: Goldflam
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, 08028, Spain.
authors.forename: Martin
authors.initials: M
authors.lastname: Kotev
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, 08028, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Ciudad
authors.affiliation: Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo, 113-8654, Japan.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hipolito
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, 08028, Spain.
authors.forename: Monica
authors.initials: M
authors.lastname: Varese
authors.affiliation: Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo, 113-8654, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Suga
authors.affiliation: Spanish National Cancer Research, Madrid, 28029, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Campos-Olivas
authors.affiliation: Department of Physical Chemistry, University of Barcelona, Barcelona, 08028, Spain.|The Institute of Biomedicine of the University of Barcelona, Barcelona, 08007, Spain.|Catalan Institution for Research and Advanced Studies, Barcelona, 08010, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Barril
authors.affiliation: Catalan Institution for Research and Advanced Studies, Barcelona, 08010, Spain.|Department of Life Sciences, Barcelona Supercomputing Center, Barcelona, 08034, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Guallar
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, 08028, Spain.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Teixidó
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, 08028, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: García
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, 08028, Spain. ernest.giralt@irbbarcelona.org.|Department of Organic Chemistry, University of Barcelona, Barcelona, 08028, Spain. ernest.giralt@irbbarcelona.org.
authors.forename: Ernest
authors.initials: E
authors.lastname: Giralt
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019151:Peptide Library; D011485:Protein Binding / Q000187:drug effects; D040262:Receptors, Vascular Endothelial Growth Factor / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001688:Biological Products; D008024:Ligands; D009842:Oligopeptides; D010446:Peptide Fragments; D019151:Peptide Library; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: drug discovery; fragment screening; growth factors; peptides; protein-protein interactions