Chalcones from Angelica keiskei (ashitaba) inhibit key Zika virus replication proteins

  • Bioorg Chem. 2022 Mar;120:105649. doi: 10.1016/j.bioorg.2022.105649.
Melina Mottin  1 ,  Lindsay K Caesar  2 ,  David Brodsky  3 ,  Nathalya C M R Mesquita  4 ,  Ketllyn Zagato de Oliveira  4 ,  Gabriela Dias Noske  3 ,  Bruna K P Sousa  5 ,  Paulo R P S Ramos  5 ,  Hannah Jarmer  3 ,  Bonnie Loh  3 ,  Kimberley M Zorn  6 ,  Daniel H Foil  6 ,  Pedro M Torres  7 ,  Rafael V C Guido  4 ,  Glaucius Oliva  4 ,  Frank Scholle  3 ,  Sean Ekins  6 ,  Nadja B Cech  2 ,  Carolina H Andrade  8 ,  Scott M Laster  9
Affiliations
  • 1. 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.
  • 2. Department of Chemistry & Biochemistry, University of North Carolina Greensboro, NC, USA.
  • 3. Department of Biological Sciences, and the Comparative Medicine Institute CAVE Program, North Carolina State University, Raleigh, NC, USA.
  • 4. São Carlos Institute of Physics, University of São Paulo, São Carlos, SP, Brazil.
  • 5. Laboratory of Molecular Modeling and Drug Design, LabMol, Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, GO, Brazil.
  • 6. Collaborations Pharmaceuticals, Inc, NC, USA.
  • 7. Laboratório de Modelagem e Dinâmica Molecular, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
  • 8. Laboratory of Molecular Modeling and Drug Design, LabMol, Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, GO, Brazil. Electronic address: [email protected].
  • 9. Department of Biological Sciences, and the Comparative Medicine Institute CAVE Program, North Carolina State University, Raleigh, NC, USA. Electronic address: [email protected].
PMID: 35124513 DOI: 10.1016/j.bioorg.2022.105649
Abstract

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.

Keywords
Angelica keiskei; Ashitaba; Chalcones; Polymerase; Protease; Zika virus.
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