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Chalcones from Angelica keiskei (ashitaba) inhibit key Zika virus replication proteins.
Mottin, Melina; Caesar, Lindsay K; Brodsky, David; Mesquita, Nathalya C M R; de Oliveira, Ketllyn Zagato; Noske, Gabriela Dias; Sousa, Bruna K P; Ramos, Paulo R P S; Jarmer, Hannah; Loh, Bonnie; Zorn, Kimberley M; Foil, Daniel H; Torres, Pedro M; Guido, Rafael V C; Oliva, Glaucius; Scholle, Frank; Ekins, Sean; Cech, Nadja B; Andrade, Carolina H; Laster, Scott M.
Afiliação
  • Mottin M; Laboratory of Molecular Modeling and Drug Design, LabMol, Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, GO, Brazil; Laboratório de Interação Patógeno-Hospedeiro, Instituto de Ciências Biológicas, Universidade de Brasília, Brasília, Brazil.
  • Caesar LK; Department of Chemistry & Biochemistry, University of North Carolina Greensboro, NC, USA.
  • Brodsky D; Department of Biological Sciences, and the Comparative Medicine Institute CAVE Program, North Carolina State University, Raleigh, NC, USA.
  • Mesquita NCMR; São Carlos Institute of Physics, University of São Paulo, São Carlos, SP, Brazil.
  • de Oliveira KZ; São Carlos Institute of Physics, University of São Paulo, São Carlos, SP, Brazil.
  • Noske GD; Department of Biological Sciences, and the Comparative Medicine Institute CAVE Program, North Carolina State University, Raleigh, NC, USA.
  • Sousa BKP; Laboratory of Molecular Modeling and Drug Design, LabMol, Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, GO, Brazil.
  • Ramos PRPS; Laboratory of Molecular Modeling and Drug Design, LabMol, Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, GO, Brazil.
  • Jarmer H; Department of Biological Sciences, and the Comparative Medicine Institute CAVE Program, North Carolina State University, Raleigh, NC, USA.
  • Loh B; Department of Biological Sciences, and the Comparative Medicine Institute CAVE Program, North Carolina State University, Raleigh, NC, USA.
  • Zorn KM; Collaborations Pharmaceuticals, Inc, NC, USA.
  • Foil DH; Collaborations Pharmaceuticals, Inc, NC, USA.
  • Torres PM; Laboratório de Modelagem e Dinâmica Molecular, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
  • Guido RVC; São Carlos Institute of Physics, University of São Paulo, São Carlos, SP, Brazil.
  • Oliva G; São Carlos Institute of Physics, University of São Paulo, São Carlos, SP, Brazil.
  • Scholle F; Department of Biological Sciences, and the Comparative Medicine Institute CAVE Program, North Carolina State University, Raleigh, NC, USA.
  • Ekins S; Collaborations Pharmaceuticals, Inc, NC, USA.
  • Cech NB; Department of Chemistry & Biochemistry, University of North Carolina Greensboro, NC, USA.
  • Andrade CH; Laboratory of Molecular Modeling and Drug Design, LabMol, Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, GO, Brazil. Electronic address: carolina@ufg.br.
  • Laster SM; Department of Biological Sciences, and the Comparative Medicine Institute CAVE Program, North Carolina State University, Raleigh, NC, USA. Electronic address: smlaster@ncsu.edu.
Bioorg Chem ; 120: 105649, 2022 03.
Article em En | MEDLINE | ID: mdl-35124513
Zika virus (ZIKV) is a dangerous human pathogen and no antiviral drugs have been approved to date. The chalcones are a group of small molecules that are found in a number of different plants, including Angelica keiskei Koidzumi, also known as ashitaba. To examine chalcone anti-ZIKV activity, three chalcones, 4-hydroxyderricin (4HD), xanthoangelol (XA), and xanthoangelol-E (XA-E), were purified from a methanol-ethyl acetate extract from A. keiskei. Molecular and ensemble docking predicted that these chalcones would establish multiple interactions with residues in the catalytic and allosteric sites of ZIKV NS2B-NS3 protease, and in the allosteric site of the NS5 RNA-dependent RNA-polymerase (RdRp). Machine learning models also predicted 4HD, XA and XA-E as potential anti-ZIKV inhibitors. Enzymatic and kinetic assays confirmed chalcone inhibition of the ZIKV NS2B-NS3 protease allosteric site with IC50s from 18 to 50 µM. Activity assays also revealed that XA, but not 4HD or XA-E, inhibited the allosteric site of the RdRp, with an IC50 of 6.9 µM. Finally, we tested these chalcones for their anti-viral activity in vitro with Vero cells. 4HD and XA-E displayed anti-ZIKV activity with EC50 values of 6.6 and 22.0 µM, respectively, while XA displayed relatively weak anti-ZIKV activity with whole cells. With their simple structures and relative ease of modification, the chalcones represent attractive candidates for hit-to-lead optimization in the search of new anti-ZIKV therapeutics.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Chalcona / Angelica / Chalconas / Zika virus / Infecção por Zika virus Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Chalcona / Angelica / Chalconas / Zika virus / Infecção por Zika virus Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article