Avaliação do potencial antiviral de inibidores farmacológicos contra chikungunya vírus

Abstract

Chikungunya virus (CHIKV) is an arbovirus transmitted by mosquitoes of the genus Aedes, being responsible for Chikungunya fever (CHIKF) in humans. The infection is commonly characterized by fever, rashes and arthralgia which in many cases progresses to a severe and chronic condition. Between 2016 and 2019, 372 246 confirmed cases of CHIKF and 542 deaths were recorded in Brazil. Currently, there are no antivirals or vaccines available to treat or prevent CHIKV infection. In the search for new ways to treat diseases caused by viruses, the search for substances that target host proteins that interact with the virus has been highlighted and, may eventually interrupt its replication cycle. In this study, we evaluated the effects of MEK/ERK inhibitors, Selumetinib, Binimetinib and Trametinib, and the NLRP3 inhibitor, MCC950, against CHIKV. After analyzing the cytotoxicity of the inhibitors through MTT and Crystal Violet, the possible antiviral activity was evaluated by means of a plaque and Western Blot assay. Only Trametinib, at the concentration of 40 μM, reduced the CHIKV titer by 1 log10 in Vero cells, mainly affecting the late stages of its replication cycle. It was also observed that CHIKV induces increased expression of NLRP3 and phosphorylation of ERK1/2 after 12 hpi in Raw 264.7 cells. Therefore, we conclude that Trametinib is a potential alternative to treat CHIKF and obtained evidence that the MEK/ERK and NLRP3 inflammasome pathways are activated during CHIKV infection.