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Evaluation of potential therapeutically compounds for SARS-CoV-2: focus on estrogen-related compounds, autophagy modulators and ACE2

Abstract

The SARS-CoV-2 (severe acute respiratory syndrome coronavirus) pandemic has become a major global concern, mainly due to impacts on health systems in different countries and the high death rate in a short period. Many recent studies on cellular models and clinical trials have pointed out that hydroxychloroquine, a drug used in malaria, lupus and rheumatoid arthritis treatment, is a possible choice to pharmacological therapy. This compound has been able to reduce viral load in samples from some patients, but additional studies are needed to proof the effectiveness of this drug, whose mechanism of action is pH change lisosomal and consequently inhibition of autophagy process. Autophagy is a highly regulated catabolic process and fundamental for the maintenance of cellular homeostasis. Our research group has been studied de role of autophagy process modulators to combat neurodegenerative, metabolic and oncological diseases. The accumulation of epidemiological evidence indicates that the elderly population is the more vulnerable and at a higher risk of suffering complications of the disease, as well as indicating a greater prevalence of deaths in male patients. Previous reports indicate differences in the severity of the disease according to gender, and indicate that estrogen may have a physiological protective relationship against coronavirus. The objectives of this Project will be: 1) to evaluate drugs and laboratory treatment protocols focused on the modulation of autophagy and estrogen signaling; 2) evaluation of cellular vulnerability and its relation to ACE2 (angiotensin converting enzyme 2) expression; 3) study of cellular signaling pathways in SARS-CoV-2 infection. With the collaboration of a multidisciplinary team we will initially cultivate the virus and identify cell lines that might support viral replication, among them: HEK293T, BEAS, A549, among others. Viral production will be evaluated quantitatively by qPCR. Cell viability will be accessed by MTT and flow cytometry (7-AAD) assays. For the identification of compounds with antiviral potential, a library of compounds with estrogenic activity and compounds that modulates the autophagic process will be used to treat cells during SARS-CoV-2 infection, assessing the viral cargo and cell viability. ACE2 expression, which acts as a receptor for the virus to infection, and whose activity can be reduced by estrogen. In a second step, we will overexpress ACE2 in the chosen cell line, verifying if the potentialization of the infection will occur, simulating a situation of sensibilization of the cell for viral infection, a condition associated with patients more vulnerable to death as diabetics and immunodeficiency compromised patients. The mechanisms of action of the drugs will be evaluated in a subsequent step, considering the type of receptor and the signaling pathway. Thus, with the initiative and efforts of researches from different areas of knowledge (virology, pulmonary pathophysiology, cellular and molecular pharmacology) we will select therapy targets that can be applied immediately, focusing on drugs repurposing through the use "off-label" aiming to reduce the capacity of viral replication in the laboratory that could eventually be translated as therapeutic alternative for hospitalized patients, especially those at high risk group. (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)
STILHANO, ROBERTA SESSA; COSTA, ANGELICA JARDIM; NISHINO, MICHELLE SAYURI; SHAMS, SHAHIN; BARTOLOMEO, CYNTHIA SILVA; BREITHAUPT-FALOPPA, ANA CRISTINA; SILVA, EDUARDO ALEXANDRE; RAMIREZ, ANA LOPEZ; PRADO, CARLA MAXIMO; URESHINO, RODRIGO PORTES. SARS-CoV-2 and the possible connection to ERs, ACE2, and RAGE: Focus on susceptibility factors. FASEB JOURNAL, v. 34, n. 11, p. 14103-14119, . (16/20796-2, 18/16719-8, 20/04709-8, 18/06088-0)
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)

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