Atividade antiviral da piridina-3-carbohidrazida no ciclo replicativo do vírus Mayaro

Abstract

Mayaro fever is a tropical disease characterized by symptoms such as high fever, myalgia, debilitating arthralgia, and headache. It is caused by Mayaro virus (MAYV), which belongs to the Togaviridae family and the genus Alphavirus. Outbreaks of MAYV have been reported in several tropical regions, prominently in Brazil. MAYV is an arbovirus transmitted by the bite of mosquitoes of the genus Haemagogus, however, recent studies suggest that mosquitoes of the genus Aedes may also act as vectors of MAYV, which raises concerns about its potential to spread in urban areas. There are still no licensed vaccines or specific antiviral treatments available for MAYV, that highlights the urgent need for research and development of new therapeutic strategies. In this study, the antiviral activity of pyridine-3-carbohydrazide (P-3-C), also known as nicotinic acid hydrazide or nicotinohydrazide, a drug with potential anti-tuberculosis, was investigated against MAYV in vitro. Vero-E6 cells were infected with MAYV-nanoluc in the presence of the P-3-C for 24 hours, when viral replication levels were quantified by measuring nanoluciferase activity. The results demonstrated that P-3-C exhibited potent dose-dependent inhibition of MAYV infection, with EC50 of 2.8 μM and CC50 of 129.3 μM, resulting in a selectivity index (SI) of 46.1. The time of drug-addition assays demonstrated a strong inhibition of the post-entry stages of viral replication by P-3-C, highlighted by its action on viral release, with a significant reduction of 6 log10 viral RNA copies in the extracellular medium and about 2 log10 in intracellular measurements compared to control. The effects of P-3-C on the release of MAYV from host cells were also remarkable when intracellular and extracellular levels of viral RNA were compared in the treated cells, resulting in a significant reduction of 4.7 x 104 in RNA titers. Additionally, P-3-C was found to inhibit 87% of the TRLV strain of the MAYV, and 91% of CHIKV, suggesting a potential broad-spectrum activity against alphaviruses. In conclusion, the antiviral data presented here demonstrate that this compound is a promising candidate for the development of potential anti-MAYV agents.