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

Author(s):Show less -

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.

• Document type: Journal article
• Source: BIOORGANIC CHEMISTRY; v. 120, p. 12-pg., 2022-02-03.

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 NS2BNS3 protease allosteric site with IC(50)s from 18 to 50 mu M. 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 mu M. 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 mu M, 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. (AU)

• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 16/17153-2 - Structural biology and drug development against the protein NS5 Zika virus
• Grantee: Ketllyn Irene Zagato de Oliveira
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 18/19574-0 - Structural biology and drug development against the protein NS5 Zika Virus
• Grantee: Ketllyn Irene Zagato de Oliveira
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 20/12904-5 - Discovery of Plasmodium falciparum inhibitors from Cerrado plants as lead compounds candidates for malaria: integrated studies of ultra-efficient chromatography, spectroscopy, and biological assays
• Grantee: Rafael Victorio Carvalho Guido
• Support Opportunities: BIOTA-FAPESP Program - Regular Research Grants