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In vitro study of Hesperetin and Hesperidin as inhibitors of zika and chikungunya virus proteases

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Autor(es):
Eberle, Raphael J. [1, 2] ; Olivier, Danilo S. [3] ; Pacca, Carolina C. [4, 5] ; Avilla, Clarita M. S. [5] ; Nogueira, Mauricio L. [6] ; Amaral, Marcos S. [7] ; Willbold, Dieter [8, 2, 9] ; Arni, Raghuvir K. [1] ; Coronado, Monika A. [1, 2]
Número total de Autores: 9
Afiliação do(s) autor(es):
[1] Univ Estadual Paulista UNESP, Multiuser Ctr Biomol Innovat, Inst Biociencias Letras & Ciencias Exatas Ibilce, Dept Phys, Sao Jose Do Rio Preto, SP - Brazil
[2] Forschungszentrum Julich, Inst Biol Informat Proc IBI 7 Struct Biochem, Julich - Germany
[3] Fed Univ Tocantins, Araguaina, TO - Brazil
[4] FACERES Med Sch, Sao Jose Do Rio Preto - Brazil
[5] Univ Estadual Paulista UNESP, Inst Biociencias Letras & Ciencias Exatas Ibilce, Sao Jose Do Rio Preto, SP - Brazil
[6] Fac Med Sao Jose Do Rio Preto FAMERP, Sao Jose Do Rio Preto - Brazil
[7] Univ Fed Mato Grosso do Sul, Inst Phys, Campo Grande, MS - Brazil
[8] Heinrich Heine Univ Dusseldorf, Inst Phys Biol, Univ Str, Dusseldorf - Germany
[9] Forchungszentrum Julich, JuStruct Julich Ctr Struct Biol, Julich - Germany
Número total de Afiliações: 9
Tipo de documento: Artigo Científico
Fonte: PLoS One; v. 16, n. 3 MAR 4 2021.
Citações Web of Science: 0
Resumo

The potential outcome of flavivirus and alphavirus co-infections is worrisome due to the development of severe diseases. Hundreds of millions of people worldwide live under the risk of infections caused by viruses like chikungunya virus (CHIKV, genus Alphavirus), dengue virus (DENV, genus Flavivirus), and zika virus (ZIKV, genus Flavivirus). So far, neither any drug exists against the infection by a single virus, nor against co-infection. The results described in our study demonstrate the inhibitory potential of two flavonoids derived from citrus plants: Hesperetin (HST) against NS2B/NS3(pro) of ZIKV and nsP2(pro) of CHIKV and, Hesperidin (HSD) against nsP2(pro) of CHIKV. The flavonoids are noncompetitive inhibitors and the determined IC50 values are in low mu M range for HST against ZIKV NS2B/NS3(pro) (12.6 +/- 1.3 mu M) and against CHIKV nsP2(pro) (2.5 +/- 0.4 mu M). The IC50 for HSD against CHIKV nsP2(pro) was 7.1 +/- 1.1 mu M. The calculated ligand efficiencies for HST were > 0.3, which reflect its potential to be used as a lead compound. Docking and molecular dynamics simulations display the effect of HST and HSD on the protease 3D models of CHIKV and ZIKV. Conformational changes after ligand binding and their effect on the substrate-binding pocket of the proteases were investigated. Additionally, MTT assays demonstrated a very low cytotoxicity of both the molecules. Based on our results, we assume that HST comprise a chemical structure that serves as a starting point molecule to develop a potent inhibitor to combat CHIKV and ZIKV co-infections by inhibiting the virus proteases. (AU)

Processo FAPESP: 18/12659-0 - Mecanismos e Interações Moleculares de Moléculas Bioativas com a Protease NS3 do Zika Vírus - De novo drug design -
Beneficiário:Monika Aparecida Coronado
Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado
Processo FAPESP: 19/05614-3 - Identificação de moléculas bioativas que inibem a atividades dos vírus Chikungunya e Mayaro
Beneficiário:Raphael Josef Eberle
Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado
Processo FAPESP: 16/12904-0 - Mecanismos e Interações Moleculares de Moléculas Bioativas com a Protease NS3 do Zika Vírus.
Beneficiário:Monika Aparecida Coronado
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 18/07572-3 - Explorando a protease nsP2 dos vírus Chikungunya e Mayaro: estruturas e inibição.
Beneficiário:Raphael Josef Eberle
Linha de fomento: Bolsas no Brasil - Pós-Doutorado