Comparative analysis of the AT1 receptor signaling profile after activation by balanced and biased agonists by proteomic approach

• Grant number: 16/08920-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: August 01, 2016
• End date: July 31, 2019
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Claudio Miguel da Costa Neto
• Grantee: Sarah Capelupe Simões
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 12/20148-0 - Development of new ligands/drugs with selective agonism action (biased agonism) for receptors of the renin-angiotensin and kallikrein-kinin systems: new properties and new biotechnological applications, AP.TEM

Abstract

G-protein coupled receptors (GPCRs) are integral membrane proteins characterized as having seven transmembrane alpha-helices. These receptors are important targets for biomedical studies, and approximately 40% of the currently marketed drugs act on them. The angiotensin II type 1 (AT1) receptor is a GPCR, and the main receptor of the renin-angiotensin system (SRA), mediating important pathophysiological effects in different tissues and organs, and being the target of the system's main effector molecule angiotensin II (AngII). Considering the pharmacological importance of the AT1 receptor, several studies have focused on the search for selective agonists that induce the activation of a particular signaling pathway in detriment of others, as well as on understanding their roles in cell signaling. This project proposes an innovative approach to study this phenomenon, which is by proteomic analysis. Cells expressing the AT1 receptor will be stimulated with different ligands including the ones previously described as selective. Our aims are to better understand what type of cellular responses these ligands generate, which proteins are activated, and in which cellular compartment(s) the activated proteins are located. The study shows promise for identifying new drug targets and for better understanding the mechanisms involved in the selective agonism. For the project development, we will count with the active participation of Professor Vitor M. Faça, a collaborator in our Thematic Project with vast experience in proteomic analyses.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

CORRE, MICHELLE F.; BALICO-SILVA, ANDRE L.; KISS, DORA J.; FERNANDES, GUSTAVO A. B.; MARASCHIN, JHONATAN C.; PARREIRAS-E-SILVA, LUCAS T.; VARELA, MARINA T.; SIMOES, SARAH C.; BOUVIER, MICHEL; KESERU, GYORGY M.; et al. Novel potent (dihydro)benzofuranyl piperazines as human histamine receptor ligands - Functional characterization and modeling studies on H-3 and H(4 )receptors. Bioorganic & Medicinal Chemistry, v. 30, JAN 15 2021. (16/24120-3, 17/05441-6, 12/20148-0, 16/25028-3, 18/03918-2, 18/00153-5, 16/08920-0, 16/23139-2)

SIMOES, SARAH C.; BALICO-SILVA, ANDRE L.; PARREIRAS-E-SILVA, LUCAS T.; BITENCOURT, ANDRE L. B.; BOUVIER, MICHEL; COSTA-NETO, CLAUDIO M.. Signal Transduction Profiling of Angiotensin II Type 1 Receptor With Mutations Associated to Atrial Fibrillation in Humans. FRONTIERS IN PHARMACOLOGY, v. 11, DEC 22 2020. (16/08920-0, 12/20148-0, 16/24120-3, 15/50086-4)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

SIMÕES, Sarah Capelupe. Cell Proteomics analysis after AT1 receptor stimulation by ligands with diferente pharmacological profiles. 2019. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) Ribeirão Preto.