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Pharmacophoric characteristics of dengue virus NS2B/NS3pro inhibitors: a systematic review of the most promising compounds

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Abstract

Dengue virus (DENV) infection can lead to a wide range of clinical manifestations, including fatal hemorrhagic complications. There is a need to find effective pharmacotherapies to treat this disease due to the lack of specific immunotherapies and antiviral drugs. That said, the DENV NS2B/NS3pro protease complex is essential in both the viral multiplication cycle and in disease pathogenesis, and is considered a promising target for new antiviral therapies. Here, we performed a systematic review to evaluate the pharmacophoric characteristics of promising compounds against NS2B/NS3pro reported in the past 10 years. Online searches in the PUBMED/MEDLINE and SCOPUS databases resulted in 165 articles. Eight studies, which evaluated 3,384,268 molecules exhibiting protease inhibition activity, were included in this review. These studies evaluated anti-dengue activity in vitro and the IC50 and EC50 values were provided. Most compounds exhibited non-competitive inhibition. Cytotoxicity was evaluated in BHK-21, Vero, and LLC-MK2 cells, and the CC50 values obtained ranged from < 1.0 to 780.5 µM. Several groups were associated with biological activity against dengue, including nitro, catechol, halogen and ammonium quaternaries. Thus, these groups seem to be potential pharmacophores that can be further investigated to treat dengue infections.

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Acknowledgements

W.G.L and C.A.L are grateful to FAPEMIG for master’s degree fellowship.

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  1. Camyla Alves Leonel and William Gustavo Lima contributed equally to this work.

Authors and Affiliations

  1. Laboratório de Microbiologia Médica, Campus Centro-Oeste Dona Lindu, Universidade Federal de São João Del Rei (UFSJ), Rua Sebastião Gonçalves Coelho, 400, Divinópolis, Minas Gerais, CEP 35501-293, Brazil

    Camyla Alves Leonel, William Gustavo Lima, Michelli dos Santos, Ariane Coelho Ferraz & Jaqueline Maria Siqueira Ferreira

  2. Laboratório de Biologia Molecular, Campus Centro-Oeste Dona Lindu, Universidade Federal de São João Del Rei (UFSJ), Divinópolis, Minas Gerais, Brazil

    Luciana Lara dos Santos

  3. Laboratório de Química Farmacêutica Medicinal, Campus Centro-Oeste Dona Lindu, Universidade Federal de São João Del Rei (UFSJ), Divinópolis, Minas Gerais, Brazil

    Alex Gutterres Taranto

  4. Laboratório de Biologia Molecular e Celular, Departamento de Química, Biotecnologia e Engenharia de Bioprocessos (DQBIO), Campus Alto Paraopeba, Universidade Federal de São João Del Rei (UFSJ), Ouro Branco, Minas Gerais, Brazil

    Ariane Coelho Ferraz & José Carlos de Magalhães

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Correspondence to Jaqueline Maria Siqueira Ferreira.

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This study was funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (UNIVERSAL 446997/2014-5 and 449984/2014-1) and Fundação de Amparo a Pesquisa de Minas Gerais (FAPEMIG) (EDITAL APQ-00557-14).

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Leonel, C.A., Lima, W.G., dos Santos, M. et al. Pharmacophoric characteristics of dengue virus NS2B/NS3pro inhibitors: a systematic review of the most promising compounds. Arch Virol 163, 575–586 (2018). https://doi.org/10.1007/s00705-017-3641-5

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