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: carolina@ufg.br.
9 Department of Biological Sciences, and the Comparative Medicine Institute CAVE Program, North Carolina State University, Raleigh, NC, USA. Electronic address: smlaster@ncsu.edu.

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-115918

XA-E

Anti-virus Agent

Others

Infection

Name
Email *

	Sorry, but the email address you supplied was invalid.