Virtual screening and in vitro and in vivo evaluation of nicotinic receptors as a therapeutic target for SARS-CoV-2: focus on interaction with ACE2.

• Grant number: 20/13480-4
• Support Opportunities: Regular Research Grants
• Start date: April 01, 2021
• End date: March 31, 2024
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Carla Máximo Prado
• Grantee: Carla Máximo Prado
• Host Institution: Instituto de Saúde e Sociedade (ISS). Universidade Federal de São Paulo (UNIFESP). Campus Baixada Santista. Santos , SP, Brazil
• Associated researchers: Ana Cristina Breithaupt Faloppa ; Ayman K. Hamouda ; Clarice Rosa Olivo ; Daniela Goncales Galasse Rando ; Iolanda de Fátima Lopes Calvo Tibério ; Marco Antonio Maximo Prado ; Roberta Sessa Stilhano Yamaguchi ; Rodrigo Portes Ureshino ; Vania Ferreira Prado ; Wothan Tavares de Lima

Abstract

SARS-CoV-2 (Severe Acute Respiratory Syndrome, Coronavirus 2) is the virus that causes COVID-19 (Coronavirus disease 2019), declared as a pandemic in March / 2020, which in its severe form leads to death due to acute lung injury (ALI), refractory hypoxemia and the presence of microthrombi. The virus enters the cell after binding the Spike protein to ACE2 (angiotensin-converting enzyme 2). There are no vaccines and specific treatment so far, the death from COVID-19 is still high and a second wave is beginning to occur in several countries. Nicotinic acetylcholine receptors (nAChRs) appear as a potential therapeutic target. Our hypothesis is that nACRs can participate not only in the capacity for viral invasion since it can be related to an expression of ACE2, but also with a modulation of the inflammatory process. The project aims to elucidate whether from this the nAChRs can be involved in COVID-19 and search for drugs already available with the potential positive modulatory effects in these receptors. An in vitro model of SARS-CoV-2 infection will be used in pulmonary epithelial cells (BEAS and A549) with and without ACE2 overexpression. In vivo, animals with cholinergic deficiency will be submitted to LPS instillation (pulmonary) or intestinal ischemia and reperfusion (extrapulmonary) to mimic a cytokine storm and ALI, and the role of these receptors and their relationship with the expression of ACE2 will be evaluated regarding inflammatory response. Parallel to this, through virtual screening, drugs with the potential for modulation of these receptors that can be subsequently tested model models will be identified. We expected to elucidate whether nAChR can be a therapeutic target for COVID-19 and to point out drugs already available and useful for immediate use. (AU)

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)

PINHEIRO, NATHALIA M.; BANZATO, ROSANA; TIBERIO, IOLANDA; PRADO, MARCO A. M.; PRADO, VANIA F.; HAMOUDA, AYMAN K.; PRADO, CARLA M.. Acute Lung Injury in Cholinergic-Deficient Mice Supports Anti-Inflammatory Role of alpha 7 Nicotinic Acetylcholine Receptor. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 22, n. 14, JUL 2021. (18/15738-9, 20/13480-4, 19/15665-4)

COSTA, ANGELICA JARDIM; LEMES, ROBERTHA MARIANA RODRIGUES; BARTOLOMEO, CYNTHIA SILVA; NUNES, TAMIRES ALVES; PEREIRA, GABRIELA CRUZ; OLIVEIRA, RAFAELA BRITO; GOMES, ALEXANDRE LOPES; SMAILI, SORAYA SOUBHI; MACIEL, RUI MONTEIRO DE BARROS; NEWSON, LOUISE; et al. Overexpression of estrogen receptor GPER1 and G1 treatment reduces SARS-CoV-2 infection in BEAS-2B bronchial cells. Molecular and Cellular Endocrinology, v. 558, p. 8-pg., 2022-12-01. (20/04709-8, 06/60402-1, 18/06088-0, 20/13480-4, 20/06153-7, 18/02762-9, 16/20796-2, 19/10922-9)

BARTOLOMEO, CYNTHIA SILVA; LEMES, ROBERTHA MARIANA RODRIGUES; MORAIS, RAFAEL LEITE; PERERIA, GABRIELA CRUZ; NUNES, TAMIRES ALVES; COSTA, ANGELICA JARDIM; MACIEL, RUI MONTEIRO DE BARROS; BRACONI, CARLA TORRES; MARICATO, JULIANA TERZI; JANINI, LUIZ MARIO RAMOS; et al. SARS-CoV-2 infection and replication kinetics in different human cell types: The role of autophagy, cellular metabolism and ACE2 expression. Life Sciences, v. 308, p. 13-pg., 2022-09-07. (20/04709-8, 06/60402-1, 20/06153-7, 20/13480-4, 20/08943-5, 16/20796-2, 19/10922-9)