Rational drug design: development of angiogenesis inhibitors targeting VEGF and TIE1 receptor pathways

• Grant number: 22/15432-2
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: November 01, 2023
• End date: October 31, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Ricardo Jose Giordano
• Grantee: Angy Liseth Davalos Macias
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 19/25828-8 - Molecular mechanisms of angiogenesis and vascular heterogeneity, AP.TEM

Abstract

"Angiogenesis-dependent diseases", such as cancer and retinopathies, affect a large number of individuals. In addition to the suffering of these individuals, these diseases cause great socioeconomic impacts. In this context, the pharmaceutical industry has been committed to developing drugs with anti-angiogenic activity, especially with anti-VEGF activity. Although great strides have been made, available anti-VEGF drugs still lack the expected clinical efficacy, including in patients who do not respond to the drug or develop resistance. Therefore, it is necessary to look for new pharmacological alternatives for angiogenesis. This project aims to select non-peptide organic compounds that inhibit angiogenesis using virtual search applied to virtual libraries of compounds. For this, we will consider the VEGF and TIE pathways, using bioactive peptides identified by our group (MAGALHAES, 2017; MICHALOSKI et al., 2016). In the case of VEGFR1 pathways, a molecule, compound V2, has already been identified as a promising lead for the treatment of retinopathy. The objective of this postdoctoral project is to continue the development of this lead, identifying more active analogues with greater affinity for the target (VEGFR-1) and, at the same time, exploring the potential of another identified target: the TIE1 receptor (MAGALHAES, 2017). Using a TIE1 binding peptide identified by our group, and with anti-angiogenic activity, in this project, we will identify the binding site of this peptide in TIE1 to then perform virtual searches to identify new leads (such as V2) for development of a new generation of drug inhibitors: the eTKI (extracellular targeting tyrosine kinase inhibitors) (MICHALOSKI et al., 2016). (AU)