Complexo de rutênio e para-cimeno inibe o vírus Chikunguna in vitro

Abstract

Chikungunya fever is a disease caused by the Chikungunya virus (CHIKV) that is transmitted by the bite of the female of Aedessp mosquito. The symptoms include fever, muscle aches, skin rash e and severe joint pains. The disease may develop into a chronic condition and joint pain that may last for months or years. Currently, there is no effective antiviral treatment against CHIKV infection, being necessary the development of novel therapies. Treatments based on natural compounds havebeen widely studied, as many drugs were produced by using natural molecules and their derivatives.Para-cymene (pCYM) is a naturally occurring aromatic organic compound that is a common ligand for ruthenium, forming the organometallic ruthenium and pCYM complex. Organometallic complexes have shown promising as a new generation of compounds that presented relevant biological properties, however, there is a lack of knowledge concerning the anti-CHIKV activity of these complexes. In this context, the present work evaluated the effects of the ruthenium and pCYM complex ([Ru2Cl4(η6-p-cymene)2]) (RcP) and its precursors on CHIKV infection in vitro. To this, BHK21 cells were infected with CHIKV-nanoluciferase (CHIKV-nanoluc), a viral construct with the reporter gene -nanoluc, at the presence or absence of the compounds for 16 hours, and citotoxicity (MTT) and infectivity (Luciferase) rates were accessed. The results demonstrated that RcPexhibited a strong therapeutic index judged by the selective index of 43.1(ratio of cytotoxicity to antiviral potency). Antiviral effects of RcPon different stages of the CHIKV replicative cycle were investigated and the results showed that it reduced 77% of virus entry to the host cells at non-toxic concentrations. Further assays demonstrated the virucidal activity of the compound that completely knocked down virus infectivity. Molecular docking calculations were performed in order to investigate possible interactions between pCYM and CHIKVglycoproteins and results suggested bindings between pCYM and a sitelocated behind the fusion loop between glycoproteins E3 and E2. Additionally, infrared spectroscopy spectral analysisindicated interactions of RcP with CHIKV glycoproteins.This data suggests that RcP may acts on CHIKV viral particles, disrupting virus entry to the host cells. Additional analyses are being performed to evaluate the mode of action of this complex.