Discovery of novel West Nile Virus protease inhibitor based on isobenzonafuranone and triazolic derivatives of eugenol and indan-1,3-dione scaffolds


Autoři: André S. de Oliveira aff001;  Poliana A. R. Gazolla aff002;  Ana Flávia C. da S. Oliveira aff001;  Wagner L. Pereira aff002;  Lívia C. de S. Viol aff002;  Angélica F. da S. Maia aff002;  Edjon G. Santos aff001;  Ítalo E. P. da Silva aff001;  Tiago A. de Oliveira Mendes aff003;  Adalberto M. da Silva aff004;  Roberto S. Dias aff001;  Cynthia C. da Silva aff001;  Marcelo D. Polêto aff001;  Róbson R. Teixeira aff004;  Sergio O. de Paula aff001
Působiště autorů: Departamento de Biologia Geral, Universidade Federal de Viçosa, Viçosa, MG, Brazil aff001;  Instituto Federal de Educação, Ciência e Tecnologia do Norte de Minas Gerais, Fazenda Biribiri, MG, Brazil aff002;  Departamento de Bioquímica Biologia Molecular, Universidade Federal de Viçosa, Viçosa, MG, Brazil aff003;  Departamento de Química, Universidade Federal de Viçosa, Viçosa, MG, Brazil aff004;  Instituto Federal de Educação, Ciência e Tecnologia Catarinense, Araquari, SC, Brazil aff005
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223017

Souhrn

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.

Klíčová slova:

Cytotoxicity – Enzyme inhibitors – Gels – NMR spectroscopy – Proteases – Column chromatography – Thin-layer chromatography – West Nile virus


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