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

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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.

• Tipo de documento: Artigo Científico
• Fonte: BIOORGANIC CHEMISTRY; v. 120, p. 12-pg., 2022-02-03.

Resumo

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)

• Processo FAPESP: 13/07600-3 - CIBFar - Centro de Inovação em Biodiversidade e Fármacos
• Beneficiário: Glaucius Oliva
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 16/17153-2 - Biologia estrutural e desenvolvimento de fármacos contra a proteína NS5 do vírus Zika
• Beneficiário: Ketllyn Irene Zagato de Oliveira
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 18/19574-0 - Biologia estrutural e desenvolvimento de fármacos contra a proteína NS5 do Vírus Zika
• Beneficiário: Ketllyn Irene Zagato de Oliveira
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 20/12904-5 - Descoberta de inibidores de Plasmodium falciparum a partir de plantas do Cerrado como candidatos a compostos líderes para a malária: estudos integrados de cromatografia de ultra eficiência, espectroscopia e ensaios biológicos
• Beneficiário: Rafael Victorio Carvalho Guido
• Modalidade de apoio: Auxílio à Pesquisa - Programa BIOTA - Regular