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 Opportunities: Research Projects - Thematic Grants
• Start date: August 01, 2013
• End date: March 31, 2020
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Claudio Miguel da Costa Neto
• Grantee: Claudio Miguel da Costa Neto
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Pesquisadores principais: Eduardo Brandt de Oliveira ; Marcelo Damário Gomes ; Rosely Oliveira Godinho
• Associated researchers: Vitor Marcel Faça
• Associated research grant(s): 15/50086-4 - Development of biosensors for monitoring signaling in subcellular compartments: a powerful molecular tool for drug discovery, AP.R SPRINT
• 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)

Scientific publications

(14)

(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)

NAMKUNG, YOON; LEGOUILL, CHRISTIAN; KUMAR, SAHIL; CAO, YUBO; TEIXEIRA, LARISSA B.; LUKASHEVA, VIKTORIYA; GIUBILARO, JENNA; SIMOES, SARAH C.; LONGPRE, JEAN-MICHEL; DEVOST, DOMINIC; et al. 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. (12/20148-0)

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.; et al. 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. (12/20148-0, 15/50086-4)

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.; et al. 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. (12/20148-0, 13/08216-2, 15/50086-4)

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. (11/02144-4, 10/13346-4, 12/20148-0)

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. (12/20148-0)

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.; et al. 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. (12/20148-0, 17/02042-3, 16/23139-2, 16/25028-3, 13/20479-9)

DUARTE, DIEGO A.; PARREIRAS-E-SILVA, LUCAS T.; OLIVEIRA, EDUARDO B.; BOUVIER, MICHEL; COSTA-NETO, CLAUDIO M.. Angiotensin II Type 1 Receptor Tachyphylaxis Is Defined by Agonist Residence Time. Hypertension, v. 79, n. 1, p. 115-125, JAN 2022. (16/15914-6, 18/13655-9, 12/20148-0, 16/24120-3, 14/09893-0)

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)

NAMKUNG, YOON; LEGOUILL, CHRISTIAN; KUMAR, SAHIL; CAO, YUBO; TEIXEIRA, LARISSA B.; LUKASHEVA, VIKTORIYA; GIUBILARO, JENNA; SIMOES, SARAH C.; LONGPRE, JEAN-MICHEL; DEVOST, DOMINIC; et al. Functional selectivity profiling of the angiotensin II type 1 receptor using pathway-wide BRET signaling sensors. SCIENCE SIGNALING, v. 11, n. 559, p. 20-pg., 2018-12-04. (12/20148-0)

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. (12/20148-0)

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. (12/20148-0, 15/50086-4)

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)

MARIA, ANDREA GUTIERREZ; DILLEMBURG-PILLA, PATRICIA; DURAND, MARINA DE TOLEDO; FLORIANO, ELAINE MEDEIROS; MANFIOLLI, ADRIANA OLIVEIRA; RAMOS, SIMONE GUSMAO; PESQUERO, JOAO BOSCO; NAHMIAS, CLARA; COSTA-NETO, CLAUDIO M.. Activation of the Kinin B1 Receptor by Its Agonist Reduces Melanoma Metastasis by Playing a Dual Effect on Tumor Cells and Host Immune Response. FRONTIERS IN PHARMACOLOGY, v. 10, SEP 25 2019. (11/02144-4, 10/13346-4, 12/20148-0)

DUARTE, DIEGO ANGELO; PARREIRAS-E-SILVA, LUCAS TABAJARA; DE OLIVEIRA, EDUARDO BRANDT; BOUVIER, MICHEL; DA COSTA-NETO, CLAUDIO MIGUEL. Molecular Insights into Tachyphylaxis Phenomenon in the Angiotensin II Type 1 Receptor. FASEB JOURNAL, v. 32, n. 1, p. 2-pg., 2018-04-01. (14/09893-0, 12/20148-0)