Abstract
The West Nile Virus (WNV) NS2B-NS3 protease is an attractive target for the development of therapeutics against this arboviral pathogen. In the present investigation, the screening of a small library of fifty-eight synthetic compounds against the NS2-NB3 protease of WNV is described. The following groups of compounds were evaluated: 3-(2-aryl-2-oxoethyl)isobenzofuran-1(3H)-ones; eugenol derivatives bearing 1,2,3-triazolic functionalities; and indan-1,3-diones with 1,2,3-triazolic functionalities. The most promising of these was a eugenol derivative, namely 4-(3-(4-allyl-2-methoxyphenoxy)-propyl)-1-(2-bromobenzyl)-1H-1,2,3-triazole (35), which inhibited the protease with IC50 of 6.86 μmol L-1. Enzyme kinetic assays showed that this derivative of eugenol presents competitive inhibition behaviour. Molecular docking calculations predicted a recognition pattern involving the residues His51 and Ser135, which are members of the catalytic triad of the WNV NS2B-NS3 protease.
Highlights
The West Nile Virus (WNV) is a member of the same family as the Dengue virus (DENV), Zika virus (ZIKV) and Yellow Fever virus (YFV), the Flaviviridae family, Flavivirus genus
The combined potential health risk associated with arthropod-borne viruses like DENV, WNV, and ZIKV is enormous
Eugenol was extracted via hydrodistillation from cloves purchased in the local market in Vicosa, Minas Gerais state, Brazil, and subsequently purified by column chromatography. 1H- and 13C-NMR spectra were recorded on a Varian Mercury 300 MNR Spectrometer (Varian, Palo Alto, CA, United States) at 300 MHz and 75 MHz, respectively, using CDCl3, C6D6 or dimethyl sulfoxide (DMSO)-d6 as solvents
Summary
The West Nile Virus (WNV) is a member of the same family as the Dengue virus (DENV), Zika virus (ZIKV) and Yellow Fever virus (YFV), the Flaviviridae family, Flavivirus genus. They are arboviruses that present RNA as a genome [1]. Diseases caused by Flavivirus are the major causes of fatality in poverty-stricken regions across Africa, Asia and some parts of the Americas. The combined potential health risk associated with arthropod-borne viruses like DENV, WNV, and ZIKV is enormous. These arboviruses are either emerging or re-emerging in many regions [2].
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