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Evaluation of estrogen-related compounds and autophagy modulators seeking for therapeutic targets against SARS-CoV-2

Grant number: 20/06153-7
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): June 01, 2020
Effective date (End): May 31, 2022
Field of knowledge:Biological Sciences - Pharmacology - General Pharmacology
Principal Investigator:Rodrigo Portes Ureshino
Grantee:Robertha Mariana Rodrigues Lemes
Host Institution: Instituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF). Universidade Federal de São Paulo (UNIFESP). Campus Diadema. Diadema , SP, Brazil
Associated research grant:20/04709-8 - Evaluation of potential therapeutically compounds for SARS-CoV-2: focus on estrogen-related compounds, autophagy modulators and ACE2, AP.R

Abstract

At the beginning of 2020, the SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) pandemic caused major impacts on the health systems in several countries, causing the death of a large number of people. Epidemiological data shows greater vulnerability in the elderly population, especially with pre-existing pathologies such as Diabetes, with a prevalence of deaths in male patients. Thus, many previous studies (with SARS-CoV) point to differences according to the gender, indicating that estrogen is associated with greater physiological protection against the Coronavirus. Nowadays, the therapy adopted includes hydroxychloroquine, which promotes the alteration of lysosomal pH and autophagy, having been able to reduce the viral load in samples from some patients and in vitro study. However, further studies are important to prove the effectiveness of this drug. Therefore, the objectives of this project will be: 1) establishment and characterization of the appropriate cell model capable of supporting viral replication and assessment of cell viability; 2) evaluation of the estrogenic component and modulation of autophagy in reducing the replication of SARS-CoV-2 in vitro by treatment with a compound library; 3) study of the efficiency of SARS-CoV-2 replication in modulating ACE2 levels; 4) study of intracellular signaling pathways triggered by the activation or inhibition of estrogen receptors and modulation of autophagy during cellular infection by SARS-CoV-2. With the collaboration of a multidisciplinary group, we will initially cultivate the virus and identify cell lines that can support viral replication. Viral production will be assessed quantitatively by qPCR. Cell viability will be accessed by MTT assays and flow cytometry (7-AAD). For the identification of compounds with antiviral potential, a compounds library with estrogenic activity and compounds that modulate the autophagic process will be used to treat cells during SARS-CoV-2 infection, assessing viral load and cell viability. The expression of ACE2, which acts as a virus receptor for infection, and whose activity can be reduced by estrogen, will also be evaluated. In a second step, we will overexpress ACE2 in the chosen cell line, verifying whether the infection will be potentiated, simulating a situation of sensitization of the cell to viral infection, a condition associated with patients more vulnerable to death such as diabetics and those with immunodeficiencies. The mechanisms of action of the drugs will be evaluated at a later stage, considering: the type of receptor and the signaling pathway. Thus, focusing in the use of pre-existing drugs, we hope to reduce the capacity for viral replication in an in vitro model, which may eventually be translated as a therapeutic alternative for hospitalized patients, especially those in high-risk groups. (AU)

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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)
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., . (20/04709-8, 06/60402-1, 18/06088-0, 20/13480-4, 20/06153-7, 18/02762-9, 16/20796-2, 19/10922-9)
RODRIGUES LEMES, ROBERTHA MARIANA; COSTA, ANGELICA JARDIM; BARTOLOMEO, CYNTHIA SILVA; BASSANI, TAYSA BERVIAN; NISHINO, MICHELLE SAYURI; DA SILVA PEREIRA, GUSTAVO JOSE; SMAILI, SORAYA SOUBHI; DE BARROS MACIEL, RUI MONTEIRO; BRACONI, CARLA TORRES; DA CRUZ, EDGAR FERREIRA; et al. 17 beta-estradiol reduces SARS-CoV-2 infection in vitro. PHYSIOLOGICAL REPORTS, v. 9, n. 2, . (16/20796-2, 06/60402-1, 18/06088-0, 20/06153-7, 19/10922-9, 20/04709-8)
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., . (20/04709-8, 06/60402-1, 20/06153-7, 20/13480-4, 20/08943-5, 16/20796-2, 19/10922-9)

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