Structural basis for the interaction of a new compound inhibitor of angiogenesis with its VEGFR-1 receptor

• Grant number: 21/14386-4
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: February 01, 2022
• End date: December 31, 2022
• Field of knowledge: Biological Sciences - Biochemistry
• Principal Investigator: Ricardo Jose Giordano
• Grantee: Thamiris Oliveira de Souza
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The vascular endothelial growth factor (VEGF) and its receptors are the major modulators to form a new vascular network from pre-existing blood vessels, a process known as angiogenesis. Anti-VEGF therapies are a reality and an option for the treatment of angiogenesis-dependent diseases, such as cancer and some retinopathies. These therapies have as target the inhibition of VEGF or of the VEGFR-2 receptor, which is one of the main molecules responsible to activate the intracellular signaling. However, many studies have suggested that another VEGF receptor, VEGFR-1, also plays an important role in the inhibition of angiogenesis. In fact, despite its low tyrosine kinase activity, VEGFR-1 is the high-affinity receptor for VEGF and its absence leads to malformation of blood vessels. Previous studies done in our group identified peptides that inhibit VEGF receptors. More recently, based on these peptides, we found a small molecule that binds to VEGFR-1 and inhibits angiogenesis assays in vitro and in vivo. In this project, we will perform site direct mutation studies on VEGFR-1 aiming to better characterize the interaction of this small molecule inhibitor with its receptor. All together, we expect to rationally design new analogs of this compound with higher affinity for VEGFR-1 and better pharmacology proprieties than the original molecule, which could then be used to treat angiogenesis-dependent diseases.(AU)