Screening de candidatos antivirais contra coronavírus

Abstract

COVID-19 has caused more than seven million deaths globally and overwhelmed the healthcare systems of several countries. Additionally, SARS-CoV-2 infection can lead to prolonged symptoms, known as Long COVID, which affect more than 100 million people worldwide and are associated with socioeconomic impacts. The disease is linked to high viral loads, often accompanied by an exacerbated inflammatory response, characterized by a cytokine storm. Mutations in new variants of the virus are consistently associated with increased transmissibility and greater immune evasion. MHV, like SARS-CoV-2, is a betacoronavirus that has been used as a research tool in biosafety level 2 laboratories. Here, we propose the screening of various molecules with antiviral potential against coronavirus infection, including: i) the flavonoids Baicalein and its metabolite, baicalin, which have already demonstrated antiadsorption effects in the context of infection by other positive ssRNA virus; ii) the alphahelical peptide (AH-D), which targets the viral lipid envelope; iii) a nucleoside analog, DFMA. The results showed that baicalin and baicalein did not exhibit effects in reducing viral titers or in restoring cell viability in L929 cells infected with MHV-3. Therefore, further testing with these compounds was not conducted. Next, we tested the AH-D peptide, which was able to reduce MHV viral titers at concentrations starting from 50nM and SARS-CoV-2 from 125nM, also restoring the viability of L929 cells in response to MHV3 infection. In vitro assays revealed DFMA to be effective against both MHV-3 and MHV-A59, as well as SARS-CoV-2, with a Selectivity Index (SI) of 6.2. Furthermore, in vivo experiments demonstrated that DFMA significantly reduced viral loads in all three infection models and decreased levels of inflammatory mediators, including CXCL1, CCL2, and IL-6, in the lungs of infected mice. These findings suggest that DFMA holds promise as an antiviral agent not only against SARS-CoV-2 but also against other coronaviruses that may emerge.