Avaliação do reposicionamento de fármacos em modelos de infecção por betacoronavírus: efeitos anti-inflamatório e antiviral da atorvastatina, dasatinibe e resveratrol

Abstract

Betacoronaviruses are pathogens with pandemic potential, as demonstrated by the COVID-19 pandemic caused by SARS-CoV-2. The severity of COVID-19 is associated with high levels of pro-inflammatory mediators, resulting from a dysregulated immune response. The presence of comorbidities during COVID-19, including obesity, is a risk factor associated with severe outcomes. In this context, drug repurposing emerges as a viable strategy for identifying new therapeutic uses for clinically approved drugs or compounds. In this study, we investigated the anti-inflammatory and antiviral effects of the drugs atorvastatin, dasatinib, and the natural compound resveratrol in murine models of betacoronavirus infection. Additionally, we examined the therapeutic effects of resveratrol in a cafeteria diet-induced obesity model during MHV-A59 and SARS-CoV-2 infection. Atorvastatin exhibited in vitro prophylactic effects in macrophages during MHV-3 infection, reducing IL-6 and TNF cytokine levels, lowering viral titers, and interfering with replication during adsorption and internalization. Meanwhile, in vitro prophylactic or therapeutic treatment with dasatinib reduced IL-6, TNF, and CXCL2 levels, as well as MHV-3 viral titers. Pre-treatment with dasatinib interfered with viral adsorption and internalization by reducing viral titers, highlighting the importance of SRC tyrosine kinase signaling in MHV-3 infection. Post-infection treatment with dasatinib negatively modulated the SRC-MAPK-NF-ĸB signaling pathway, reducing the release of pro-inflammatory mediators by macrophages. SRC signaling may be a potential target for interventions in the control of coronavirus infections. Our results with resveratrol demonstrated its anti-inflammatory effect both in vitro, by reducing IL-6, TNF, and CXCL2 levels, and in vivo, by decreasing CCL2 and CXCL1 levels during MHV-A59 and SARS-CoV-2 infection, while preserving IFN-β at basal levels in obese animals infected with MHV-A59. We observed that resveratrol reduced viral titers in vitro, in the lungs of obese animals infected with MHV-A59, and in K18-hACE2 mice infected with SARS-CoV-2. Additionally, resveratrol decreased neutrophil counts in the blood and lungs of obese animals and reduced neutrophil activation by decreasing ROS release during MHV-A59 infection. Resveratrol also normalized plasma levels of glucose, cholesterol, triglycerides, leptin, and TNF expression in epididymal adipose tissue while upregulating adiponectin levels in obese animals infected with MHV-A59. In the visceral adipose tissue of obese animals, resveratrol reduced MHV-A59 viral load at 5 dpi. Our data suggest that atorvastatin, dasatinib, and the natural compound resveratrol represent a promising therapeutic strategy for adjunctive treatment of coronavirus infections, as evidenced by their anti-inflammatory and antiviral effects.