Discovery of pan-VEGF inhibitory peptides directed to the extracellular ligand-binding domains of the VEGF receptors.
Receptor tyrosine kinases (RTKs) are key molecules in numerous cellular processes, the inhibitors of which play an important role in the clinic. Among them are the vascular endothelial growth factor (VEGF) family members and their receptors (VEGFR), which are essential in the formation of new blood vessels by angiogenesis. Anti-VEGF therapy has already shown promising results in oncology and ophthalmology, but one of the challenges in the field is the design of specific small-molecule inhibitors for these receptors. We show the identification and characterization of small 6-mer peptides that target the extracellular ligand-binding domain of all three VEGF receptors. These peptides specifically prevent the binding of VEGF family members to all three receptors and downstream signaling but do not affect other angiogenic RTKs and their ligands. One of the selected peptides was also very effective at preventing pathological angiogenesis in a mouse model of retinopathy, normalizing the vasculature to levels similar to those of a normal developing retina. Collectively, our results suggest that these peptides are pan-VEGF inhibitors directed at a common binding pocket shared by all three VEGFRs. These peptides and the druggable binding site they target might be important for the development of novel and selective small-molecule, extracellular ligand-binding inhibitors of RTKs (eTKIs) for angiogenic-dependent diseases.
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, P.O. Box 26077, CEP 05513-970, São Paulo, Brazil.
Jussara S
JS
Michaloski
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, P.O. Box 26077, CEP 05513-970, São Paulo, Brazil.
Alexandre R
0000-0003-3023-5698
AR
Redondo
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, P.O. Box 26077, CEP 05513-970, São Paulo, Brazil.
Leila S
LS
Magalhães
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, P.O. Box 26077, CEP 05513-970, São Paulo, Brazil.
Caio C
CC
Cambui
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, P.O. Box 26077, CEP 05513-970, São Paulo, Brazil.
Ricardo J
0000-0001-8116-6771
RJ
Giordano
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D000818:Animals; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D019151:Peptide Library; D000072417:Protein Domains; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015861:Retinal Neovascularization / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D019151:Peptide Library; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor