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Article

Commercially Available Flavonols Are Better SARS-CoV-2 Inhibitors than Isoflavone and Flavones

1
Laboratory of Immunopharmacology, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil
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National Institute for Science and Technology on Innovation on Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil
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Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY 10027, USA
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Department of Chemical Engineering, Columbia University, New York, NY 10027, USA
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Laboratory on Thymus Research, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil
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National Institute for Science and Technology on Neuroimmunomodulation (INCT/NIM), Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil
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Preclinical Research Laboratory, Universidade Iguaçu—UNIG, Nova Iguaçu 26260-045, Brazil
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Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, NY 10032, USA
*
Authors to whom correspondence should be addressed.
Academic Editors: Zhengqiang Wang and Robert J. Geraghty
Viruses 2022, 14(7), 1458; https://doi.org/10.3390/v14071458
Received: 10 June 2022 / Revised: 28 June 2022 / Accepted: 29 June 2022 / Published: 30 June 2022
(This article belongs to the Special Issue Viral Nucleases)
Despite the fast development of vaccines, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still circulating and generating variants of concern (VoC) that escape the humoral immune response. In this context, the search for anti-SARS-CoV-2 compounds is still essential. A class of natural polyphenols known as flavonoids, frequently available in fruits and vegetables, is widely explored in the treatment of different diseases and used as a scaffold for the design of novel drugs. Therefore, herein we evaluate seven flavonoids divided into three subclasses, isoflavone (genistein), flavone (apigenin and luteolin) and flavonol (fisetin, kaempferol, myricetin, and quercetin), for COVID-19 treatment using cell-based assays and in silico calculations validated with experimental enzymatic data. The flavonols were better SARS-CoV-2 inhibitors than isoflavone and flavones. The increasing number of hydroxyl groups in ring B of the flavonols kaempferol, quercetin, and myricetin decreased the 50% effective concentration (EC50) value due to their impact on the orientation of the compounds inside the target. Myricetin and fisetin appear to be preferred candidates; they are both anti-inflammatory (decreasing TNF-α levels) and inhibit SARS-CoV-2 mainly by targeting the processability of the main protease (Mpro) in a non-competitive manner, with a potency comparable to the repurposed drug atazanavir. However, fisetin and myricetin might also be considered hits that are amenable to synthetic modification to improve their anti-SARS-CoV-2 profile by inhibiting not only Mpro, but also the 3′–5′ exonuclease (ExoN). View Full-Text
Keywords: SARS-CoV-2; COVID-19; natural product; flavonoids; molecular docking; calu-3 cells; exonuclease; protease SARS-CoV-2; COVID-19; natural product; flavonoids; molecular docking; calu-3 cells; exonuclease; protease
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MDPI and ACS Style

Chaves, O.A.; Fintelman-Rodrigues, N.; Wang, X.; Sacramento, C.Q.; Temerozo, J.R.; Ferreira, A.C.; Mattos, M.; Pereira-Dutra, F.; Bozza, P.T.; Castro-Faria-Neto, H.C.; Russo, J.J.; Ju, J.; Souza, T.M.L. Commercially Available Flavonols Are Better SARS-CoV-2 Inhibitors than Isoflavone and Flavones. Viruses 2022, 14, 1458. https://doi.org/10.3390/v14071458

AMA Style

Chaves OA, Fintelman-Rodrigues N, Wang X, Sacramento CQ, Temerozo JR, Ferreira AC, Mattos M, Pereira-Dutra F, Bozza PT, Castro-Faria-Neto HC, Russo JJ, Ju J, Souza TML. Commercially Available Flavonols Are Better SARS-CoV-2 Inhibitors than Isoflavone and Flavones. Viruses. 2022; 14(7):1458. https://doi.org/10.3390/v14071458

Chicago/Turabian Style

Chaves, Otávio Augusto, Natalia Fintelman-Rodrigues, Xuanting Wang, Carolina Q. Sacramento, Jairo R. Temerozo, André C. Ferreira, Mayara Mattos, Filipe Pereira-Dutra, Patrícia T. Bozza, Hugo Caire Castro-Faria-Neto, James J. Russo, Jingyue Ju, and Thiago Moreno L. Souza. 2022. "Commercially Available Flavonols Are Better SARS-CoV-2 Inhibitors than Isoflavone and Flavones" Viruses 14, no. 7: 1458. https://doi.org/10.3390/v14071458

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