Abstract
Chikungunya fever is a disease caused by the Chikungunya virus (CHIKV) that is transmitted by the bite of the female of Aedes sp. mosquito. The symptoms include fever, muscle aches, skin rash, and severe joint pains. The disease may develop into a chronic condition and joint pain for months or years. Currently, there is no effective antiviral treatment against CHIKV infection. Treatments based on natural compounds have been widely studied, as many drugs were produced by using natural molecules and their derivatives. Alpha-phellandrene (α-Phe) is a naturally occurring organic compound that is a ligand for ruthenium, forming the organometallic complex [Ru2Cl4(p-cymene)2] (RcP). Organometallic complexes have shown promising as candidate molecules to 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. The present work evaluated the effects of the RcP and its precursors, the hydrate ruthenium(III) chloride salt (RuCl3⋅xH2O) (Ru) and α-Phe, on CHIKV infection in vitro. To this, BHK-21 cells were infected with CHIKV-nanoluciferase (CHIKV-nanoluc), a viral construct harboring the nanoluciferase reporter gene, at the presence or absence of the compounds for 16 h. Cytotoxicity and impact on infectivity were analyzed. The results demonstrated that RcP exhibited a strong therapeutic potential judged by the selective index > 40. Antiviral effects of RcP on different stages of the CHIKV replicative cycle were investigated; the results showed that it affected early stages of virus infection reducing virus replication by 77% at non-cytotoxic concentrations. Further assays demonstrated the virucidal activity of the compound that completely blocked virus infectivity. In silico molecular docking calculations suggested different binding interactions between aromatic rings of RcP and the loop of amino acids of the E2 envelope CHIKV glycoprotein mainly through hydrophobic interactions. Additionally, infrared spectroscopy spectral analysis indicated interactions of RcP with CHIKV glycoproteins. These data suggest that RcP may act on CHIKV particles, disrupting virus entry to the host cells. Therefore, RcP may represent a strong candidate for the development of anti-CHIKV drugs.
Highlights
The Chikungunya virus (CHIKV) belongs to the genus Alphavirus of the family Togaviridae (Chen et al, 2018; ICTV, 2019)
Since ruthenium complexes were shown to possess antimicrobial properties (Pavan et al, 2010), we aimed to investigate the antiCHIKV activity of the RcP (Figure 1A) by using a recombinant CHIKV that expresses the nanoluciferase reporter (CHIKVnanoluc) (Figure 1B)
To assess the effect of RcP on cell viability and virus infection, we performed a dose response assay to determine the effective concentration of 50% (EC50) and the cytotoxicity concentration of 50% (CC50) values for RcP
Summary
The Chikungunya virus (CHIKV) belongs to the genus Alphavirus of the family Togaviridae (Chen et al, 2018; ICTV, 2019). It is a positive strand RNA virus with a genome of approximately 12 kb (Schuffenecker et al, 2006). In 2006, CHIKV outbreaks were reported on several Indian Ocean islands and resulted in about 250 deaths on the French island of La Réunion (Schuffenecker et al, 2006). In 2013, the virus was detected in the Americas with reported cases in the Caribbean islands (Kaur and Chu, 2013). The first case in Brazil was reported in 2014 (Carvalho et al, 2014)
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