Characterization of peptides that interact with receptor tyrosine kinase VEGFR-3

• Grant number: 12/18681-1
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: January 01, 2013
• End date: December 31, 2013
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Ricardo Jose Giordano
• Grantee: Caio Cesar Nogueira Cambui
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 08/54806-8 - Identification of new molecular markers in angiogenic retina and rational design of new therapeutic agents for eye diseases with a vascular component, AP.JP

Abstract

Angiogenesis, the growth of new blood vessels from pre-existing vasculature, has an essential role in physiological repair processes such as wound healing and the female reproductive cycle. However, angiogenesis also occurs in several pathological conditions, including tumor growth, retinopathies, and other angiogenesis-dependent diseases. Vascular endothelial growth factor (VEGF) stimulates angiogenesis by activating VEGF receptor (VEGFR) tyrosine kinases in endothelial cells. Anti-VEGF therapies are being used in some cancer therapies and also in the treatment of age-related macular degeneration to inhibit pathological angiogenesis. However, anti-VEGF therapy presents several adverse effects such as high blood pressure and cardiac disorders. The challenge for the effectiveness of anti-VEGF therapies is inhibiting selectively the pathological angiogenesis without disturbing normal endothelial cells homeostasis. We propose to search for anti-angiogenic compounds more selective and with fewer adverse effects. Our strategy is to identify new targets that play a role in pathological angiogenesis without affecting endothelial cell homeostasis. VEGFR-3 receptor is an attractive target because it is highly expressed in endothelial tip cells and plays an important role in angiogenesis sprouting. Using Phage Display technology, which allows displaying peptides repertoires on the surface of bacteriophages, two peptides were specifically selected against the VEGFR-3 receptor. We are going to determine the contribution of each amino acid residue to the receptor-peptide interaction in vitro and define the receptor's domains important for peptide ligand recognition. The characterization of the structure peptide-binding receptor may collaborate for the development of peptidomimetics or drugs for more successful angiogenic therapies.(AU)