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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

Grant number: 12/20148-0
Support type:Research Projects - Thematic Grants
Duration: August 01, 2013 - July 31, 2019
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Claudio Miguel da Costa Neto
Grantee:Claudio Miguel da Costa Neto
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Co-Principal Investigators:Eduardo Brandt de Oliveira ; Marcelo Damário Gomes ; Rosely Oliveira Godinho
Assoc. researchers:Vitor Marcel Faça
Associated grant(s):15/50086-4 - Development of biosensors for monitoring signaling in subcellular compartments: a powerful molecular tool for drug discovery, AP.R
Associated scholarship(s):18/13655-9 - Space-time characterization of g protein-coupled receptors (GPCRs) signal transduction through new bioluminescence resonance energy transfer (BRET)-based biosensors, BP.PD
18/10440-1 - Identification and characterization of new phosphatases from the MAPK / ERK pathway, BP.DR
16/08920-0 - Comparative analysis of the AT1 receptor signaling profile after activation by balanced and biased agonists by proteomic approach, BP.DR
+ associated scholarships 15/14194-7 - New ligands of angiotensin II AT1 receptor with non-canonical signaling pathways activation potential: large-scale development and characterization, BP.PD
14/20906-7 - Identification of molecular partners from Angiotensin II receptor type 1 (AT1) involved with the activation of a new signaling pathway, BP.PD
14/09893-0 - Design and synthesis of novel AT1 receptor ligands: biochemical and pharmacological characterization in search of biased agonists (biased agonists), BP.DR
13/15495-5 - Investigation of the role of AT1 receptor biased agonists at formation of signaling complex ligand-receptor-Beta-arrestin-kinase, BP.PD
13/01261-2 - Involvement of biased agonism on trafficking and signaling of Angiotensin II AT1 receptor, BP.PD - associated scholarships

Abstract

In the last years it has been strongly highlighted in the literature the important role of the so called "local "renin-angiotensin (RA) and kallikrein-kinin (KK) systems (i.e., present in tissues and organs that are originally unrelated to the classical functions of those systems. The classical roles of RAS and KKS include the control of arterial blood pressure and fluid balance through the action of its vasoactive peptides on G-protein coupled receptors (GPCRs), also known as 7TM receptors. The participation of RA and KK systems, and their receptors in pathological situations that are not related to the classical functions of these systems have been described in the literature (for review see Paul et al., 2006; Costa-Neto et al., 2008), including results from our group on involvement in epilepsy (Pereira et al., 2008, Pereira et al., 2010, Pereira et al., submitted - Hypertension), inflammation (Souza et al., 2007; Souza and Costa-Neto, 2012 ), and cancer (Rodriguez-Ferreira et al., 2012b; Rodrigues-Ferreira et al., 2012b; Dillenburg-Pilla et al., submitted - PloS One). One of the possible explanation for the high medical-pharmaceutical relevance of GPCRs (N.B. about 50% of currently marketed drugs act directly or indirectly by modulating the action of GPCRs), including the diverse functions of these receptors, is their ability to activate different signaling pathways, often with different intensities or even selectively, what is called selective agonism or more currently "biased agonism". Based on that, the main goal of this project is to develop and characterize new ligands/drugs with selective agonistic activity for GPCRs from the RA and KK systems, which then showing to possess pharmacological and functional relevance will enable future biotechnological applications. The new developed agonists will be characterized in cells with heterologous expression of wild-type GPCRs, as previously described by our group (e.g. Costa-Neto et al., 2000, Santos et al., 2004; Reis et al., 2007; Santos et al., 2007; Santos et al., 2008; Oliveira et al., 2011; Reis et al., submitted - PNAS). In a second stage of this project, after the thorough pharmacological and biochemical characterization of the new agonists mechanism of action, those compounds will be evaluated for their actions to regulate the expression of different molecular downstream targets by using transcriptomic microarrays and non-directed proteomic approaches. We believe that the success of this project will allow: i) the discovery of new ligands/drugs with selective properties with pharmaco/biotechnological applications, ii) development of a solid structure for biotechnological development and future discovery of new ligands/drugs with selective action. (AU)

Articles published in Agência FAPESP about the research grant
Biosensors make new approaches to drug discovery possible 

Scientific publications (8)
(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)
SILVA, RAFAELA R.; PARREIRAS-E-SILVA, LUCAS T.; POMPEU, THAIS E. T.; DUARTE, DIEGO A.; FRAGA, CARLOS A. M.; BARREIRO, ELIEZER J.; MENEGATTI, RICARDO; COSTA-NETO, CLAUDIO M.; NOEL, FRANCOIS. Evaluation of Functional Selectivity of Haloperidol, Clozapine, and LASSBio-579, an Experimental Compound With Antipsychotic-Like Actions in Rodents, at G Protein and Arrestin Signaling Downstream of the Dopamine D-2 Receptor. FRONTIERS IN PHARMACOLOGY, v. 10, JUN 4 2019. Web of Science Citations: 0.
NAMKUNG, YOON; LEGOUILL, CHRISTIAN; KUMAR, SAHIL; CAO, YUBO; TEIXEIRA, LARISSA B.; LUKASHEVA, VIKTORIYA; GIUBILARO, JENNA; SIMOES, SARAH C.; LONGPRE, JEAN-MICHEL; DEVOST, DOMINIC; HEBERT, TERENCE E.; PINEYRO, GRACIELA; LEDUC, RICHARD; COSTA-NETO, CLAUDIO M.; BOUVIER, MICHEL; LAPORTE, STEPHANE A. Functional selectivity profiling of the angiotensin II type 1 receptor using pathway-wide BRET signaling sensors. Science Signaling, v. 11, n. 559 DEC 4 2018. Web of Science Citations: 1.
CORREA, MICHELLE F.; BARBOSA, ALEFE J. R.; TEIXEIRA, LARISSA B.; DUARTE, DIEGO A.; SIMOES, SARAH C.; PARREIRAS-E-SILVA, LUCAS T.; BALBINO, ALEKSANDRO M.; LANDGRAF, RICHARDT G.; BOUVIER, MICHEL; COSTA-NETO, CLAUDIO M.; FERNANDES, JOAO P. S. Pharmacological Characterization of 5-Substituted 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazines: Novel Antagonists for the Histamine H-3 and H-4 Receptors with Anti-inflammatory Potential. FRONTIERS IN PHARMACOLOGY, v. 8, NOV 14 2017. Web of Science Citations: 2.
TEIXEIRA, LARISSA B.; PARREIRAS-E-SILVA, LUCAS T.; BRUDER-NASCIMENTO, THIAGO; DUARTE, DIEGO A.; SIMOES, SARAH C.; COSTA, RAFAEL M.; RODRIGUEZ, DEISY Y.; FERREIRA, PEDRO A. B.; SILVA, CARLOS A. A.; ABRAO, EMILIANA P.; OLIVEIRA, EDUARDO B.; BOUVIER, MICHEL; TOSTES, RITA C.; COSTA-NETO, CLAUDIO M. Ang-(1-7) is an endogenous beta-arrestin-biased agonist of the AT(1) receptor with protective action in cardiac hypertrophy. SCIENTIFIC REPORTS, v. 7, SEP 19 2017. Web of Science Citations: 14.
PARREIRAS-E-SILVA, LUCAS T.; VARGAS-PINILLA, PEDRO; DUARTE, DIEGO A.; LONGO, DANAE; ESPINOZA PARDO, GRACE VIOLETA; FINKLER, ANDREA DULOR; PAIXAO-CORTES, VANESSA RODRIGUES; PARE, PAMELA; ROVARIS, DIEGO L.; OLIVEIRA, EDUARDO B.; CACERES, RAFAEL ANDRADE; GONCALVES, GISLENE L.; BOUVIER, MICHEL; SALZANO, FRANCISCO M.; LUCION, ALDO B.; COSTA-NETO, CLAUDIO M.; BORTOLINI, MARIA CATIRA. Functional New World monkey oxytocin forms elicit an altered signaling profile and promotes parental care in rats. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v. 114, n. 34, p. 9044-9049, AUG 22 2017. Web of Science Citations: 10.
COSTA-NETO, CLAUDIO M.; PARREIRAS-E-SILVA, LUCAS T.; BOUVIER, MICHEL. A Pluridimensional View of Biased Agonism. MOLECULAR PHARMACOLOGY, v. 90, n. 5, p. 587-595, NOV 1 2016. Web of Science Citations: 29.
MARIA, ANDREA G.; DILLENBURG-PILLA, PATRICIA; REIS, ROSANA I.; FLORIANO, ELAINE M.; TEFE-SILVA, CRISTIANE; RAMOS, SIMONE G.; PESQUERO, JOAO B.; NAHMIAS, CLARA; COSTA-NETO, CLAUDIO M. Host kinin B1 receptor plays a protective role against melanoma progression. SCIENTIFIC REPORTS, v. 6, FEB 22 2016. Web of Science Citations: 0.
SANTOS, GEISA A.; DUARTE, DIEGO A.; PARREIRAS-E-SILVA, LUCAS T.; TEIXEIRA, FELIPE R.; SILVA-ROCHAY, RAFAEL; OLIVEIRA, EDUARDO B.; BOUVIER, MICHEL; COSTA-NETO, CLAUDIO M. Comparative analyses of downstream signal transduction targets modulated after activation of the AT(1) receptor by two beta-arrestin-biased agonists. FRONTIERS IN PHARMACOLOGY, v. 6, JUL 1 2015. Web of Science Citations: 11.

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