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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.

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)