{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:18:29Z","timestamp":1791317909961,"version":"4.3.1"},"reference-count":46,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,6,30]],"date-time":"2022-06-30T00:00:00Z","timestamp":1656547200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIAID-NIH)","award":["U19AI171401"],"award-info":[{"award-number":["U19AI171401"]}]},{"name":"National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIAID-NIH)","award":["441019\/2020-0"],"award-info":[{"award-number":["441019\/2020-0"]}]},{"name":"National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIAID-NIH)","award":["307162\/2017-6"],"award-info":[{"award-number":["307162\/2017-6"]}]},{"name":"National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIAID-NIH)","award":["E-26\/210.182\/2020"],"award-info":[{"award-number":["E-26\/210.182\/2020"]}]},{"name":"National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIAID-NIH)","award":["E-26\/201.067\/2021"],"award-info":[{"award-number":["E-26\/201.067\/2021"]}]},{"name":"National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIAID-NIH)","award":["E-26\/210.112\/2020"],"award-info":[{"award-number":["E-26\/210.112\/2020"]}]},{"name":"National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIAID-NIH)","award":["88887.506989\/2020-00"],"award-info":[{"award-number":["88887.506989\/2020-00"]}]},{"name":"National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIAID-NIH)","award":["465313\/2014-0"],"award-info":[{"award-number":["465313\/2014-0"]}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["U19AI171401"],"award-info":[{"award-number":["U19AI171401"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["441019\/2020-0"],"award-info":[{"award-number":["441019\/2020-0"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["307162\/2017-6"],"award-info":[{"award-number":["307162\/2017-6"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["E-26\/210.182\/2020"],"award-info":[{"award-number":["E-26\/210.182\/2020"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["E-26\/201.067\/2021"],"award-info":[{"award-number":["E-26\/201.067\/2021"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["E-26\/210.112\/2020"],"award-info":[{"award-number":["E-26\/210.112\/2020"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["88887.506989\/2020-00"],"award-info":[{"award-number":["88887.506989\/2020-00"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["465313\/2014-0"],"award-info":[{"award-number":["465313\/2014-0"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004586","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro","doi-asserted-by":"publisher","award":["U19AI171401"],"award-info":[{"award-number":["U19AI171401"]}],"id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004586","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro","doi-asserted-by":"publisher","award":["441019\/2020-0"],"award-info":[{"award-number":["441019\/2020-0"]}],"id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004586","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro","doi-asserted-by":"publisher","award":["307162\/2017-6"],"award-info":[{"award-number":["307162\/2017-6"]}],"id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004586","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro","doi-asserted-by":"publisher","award":["E-26\/210.182\/2020"],"award-info":[{"award-number":["E-26\/210.182\/2020"]}],"id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004586","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro","doi-asserted-by":"publisher","award":["E-26\/201.067\/2021"],"award-info":[{"award-number":["E-26\/201.067\/2021"]}],"id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004586","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro","doi-asserted-by":"publisher","award":["E-26\/210.112\/2020"],"award-info":[{"award-number":["E-26\/210.112\/2020"]}],"id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004586","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro","doi-asserted-by":"publisher","award":["88887.506989\/2020-00"],"award-info":[{"award-number":["88887.506989\/2020-00"]}],"id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004586","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro","doi-asserted-by":"publisher","award":["465313\/2014-0"],"award-info":[{"award-number":["465313\/2014-0"]}],"id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["U19AI171401"],"award-info":[{"award-number":["U19AI171401"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["441019\/2020-0"],"award-info":[{"award-number":["441019\/2020-0"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["307162\/2017-6"],"award-info":[{"award-number":["307162\/2017-6"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["E-26\/210.182\/2020"],"award-info":[{"award-number":["E-26\/210.182\/2020"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["E-26\/201.067\/2021"],"award-info":[{"award-number":["E-26\/201.067\/2021"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["E-26\/210.112\/2020"],"award-info":[{"award-number":["E-26\/210.112\/2020"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["88887.506989\/2020-00"],"award-info":[{"award-number":["88887.506989\/2020-00"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["465313\/2014-0"],"award-info":[{"award-number":["465313\/2014-0"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institutes of Science and Technology Program (INCT) on Diseases of Neglected Populations","award":["U19AI171401"],"award-info":[{"award-number":["U19AI171401"]}]},{"name":"National Institutes of Science and Technology Program (INCT) on Diseases of Neglected Populations","award":["441019\/2020-0"],"award-info":[{"award-number":["441019\/2020-0"]}]},{"name":"National Institutes of Science and Technology Program (INCT) on Diseases of Neglected Populations","award":["307162\/2017-6"],"award-info":[{"award-number":["307162\/2017-6"]}]},{"name":"National Institutes of Science and Technology Program (INCT) on Diseases of Neglected Populations","award":["E-26\/210.182\/2020"],"award-info":[{"award-number":["E-26\/210.182\/2020"]}]},{"name":"National Institutes of Science and Technology Program (INCT) on Diseases of Neglected Populations","award":["E-26\/201.067\/2021"],"award-info":[{"award-number":["E-26\/201.067\/2021"]}]},{"name":"National Institutes of Science and Technology Program (INCT) on Diseases of Neglected Populations","award":["E-26\/210.112\/2020"],"award-info":[{"award-number":["E-26\/210.112\/2020"]}]},{"name":"National Institutes of Science and Technology Program (INCT) on Diseases of Neglected Populations","award":["88887.506989\/2020-00"],"award-info":[{"award-number":["88887.506989\/2020-00"]}]},{"name":"National Institutes of Science and Technology Program (INCT) on Diseases of Neglected Populations","award":["465313\/2014-0"],"award-info":[{"award-number":["465313\/2014-0"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>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-\u03b1 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\u2032\u20135\u2032 exonuclease (ExoN).<\/jats:p>","DOI":"10.3390\/v14071458","type":"journal-article","created":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T01:40:36Z","timestamp":1656639636000},"page":"1458","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Commercially Available Flavonols Are Better SARS-CoV-2 Inhibitors than Isoflavone and Flavones"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6211-7659","authenticated-orcid":false,"given":"Ot\u00e1vio Augusto","family":"Chaves","sequence":"first","affiliation":[{"name":"Laboratory of Immunopharmacology, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil"},{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2332-8338","authenticated-orcid":false,"given":"Natalia","family":"Fintelman-Rodrigues","sequence":"additional","affiliation":[{"name":"Laboratory of Immunopharmacology, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil"},{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4198-7388","authenticated-orcid":false,"given":"Xuanting","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY 10027, USA"},{"name":"Department of Chemical Engineering, Columbia University, New York, NY 10027, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3952-7099","authenticated-orcid":false,"given":"Carolina Q.","family":"Sacramento","sequence":"additional","affiliation":[{"name":"Laboratory of Immunopharmacology, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil"},{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8092-2149","authenticated-orcid":false,"given":"Jairo R.","family":"Temerozo","sequence":"additional","affiliation":[{"name":"Laboratory on Thymus Research, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil"},{"name":"National Institute for Science and Technology on Neuroimmunomodulation (INCT\/NIM), Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9 C.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Laboratory of Immunopharmacology, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil"},{"name":"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"},{"name":"Preclinical Research Laboratory, Universidade Igua\u00e7u\u2014UNIG, Nova Igua\u00e7u 26260-045, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayara","family":"Mattos","sequence":"additional","affiliation":[{"name":"Laboratory of Immunopharmacology, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil"},{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1917-2876","authenticated-orcid":false,"given":"Filipe","family":"Pereira-Dutra","sequence":"additional","affiliation":[{"name":"Laboratory of Immunopharmacology, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8349-9529","authenticated-orcid":false,"given":"Patr\u00edcia T.","family":"Bozza","sequence":"additional","affiliation":[{"name":"Laboratory of Immunopharmacology, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo Caire","family":"Castro-Faria-Neto","sequence":"additional","affiliation":[{"name":"Laboratory of Immunopharmacology, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James J.","family":"Russo","sequence":"additional","affiliation":[{"name":"Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY 10027, USA"},{"name":"Department of Chemical Engineering, Columbia University, New York, NY 10027, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4974-4241","authenticated-orcid":false,"given":"Jingyue","family":"Ju","sequence":"additional","affiliation":[{"name":"Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY 10027, USA"},{"name":"Department of Chemical Engineering, Columbia University, New York, NY 10027, USA"},{"name":"Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thiago Moreno L.","family":"Souza","sequence":"additional","affiliation":[{"name":"Laboratory of Immunopharmacology, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil"},{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,30]]},"reference":[{"key":"ref_1","unstructured":"(2022, May 31). COVID-19 Dashboardby the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU). Available online: https:\/\/coronavirus.jhu.edu\/map.html."},{"key":"ref_2","unstructured":"(2022, May 15). Coronavirus (COVID-19)|Drugs, Available online: https:\/\/www.fda.gov\/drugs\/emergency-preparedness-drugs\/coronavirus-covid-19-drugs."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"eabj5365","DOI":"10.1126\/sciadv.abj5365","article-title":"Emerging SARS-CoV-2 variants of concern evade humoral immune responses from infection and vaccination","volume":"7","author":"Caniels","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e220446","DOI":"10.1001\/jamaoncol.2022.0446","article-title":"Humoral responses against variants of concern by COVID-19 mRNA vaccines in immunocompromised patients","volume":"8","author":"Obeid","year":"2022","journal-title":"JAMA Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2372","DOI":"10.1016\/j.cell.2021.03.013","article-title":"Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity","volume":"184","author":"Lam","year":"2021","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"eabj1750","DOI":"10.1126\/sciimmunol.abj1750","article-title":"SARS-CoV-2 variants of concern partially escape humoral but not T-cell responses in COVID-19 convalescent donors and vaccinees","volume":"6","author":"Geers","year":"2021","journal-title":"Sci. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"100280","DOI":"10.1016\/j.phyplu.2022.100280","article-title":"Herbal medications and natural products for patients with covid-19 and diabetes mellitus: Potentials and challenges","volume":"2","author":"Yusuf","year":"2022","journal-title":"Phytomed. Plus"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"815388","DOI":"10.3389\/fviro.2021.815388","article-title":"SARS-CoV-2 and the host cell: A tale of interactions","volume":"1","author":"Pizzato","year":"2022","journal-title":"Front. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"105241","DOI":"10.1016\/j.compbiomed.2022.105241","article-title":"Systems pharmacology-based drug discovery and active mechanism of natural products for coronavirus pneumonia (COVID-19): An example using flavonoids","volume":"26","author":"Wang","year":"2022","journal-title":"Comput. Biol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1038\/s42003-022-03101-9","article-title":"Combination of antiviral drugs to inhibit SARS-CoV-2 polymerase and exonuclease as potential COVID-19 therapeutics","volume":"5","author":"Wang","year":"2022","journal-title":"Commun. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"634047","DOI":"10.3389\/fphar.2021.634047","article-title":"Discovering potential RNA dependent RNA polymerase inhibitors as prospective drugs against COVID-19: An in silico approach","volume":"12","author":"Saha","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"16711","DOI":"10.1039\/D1RA00644D","article-title":"A review on potential of natural products in the management of COVID-19","volume":"11","author":"Chakravarti","year":"2021","journal-title":"RSC Adv."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"588654","DOI":"10.3389\/fphar.2020.588654","article-title":"Challenges for drug repurposing in the COVID-19 pandemic era","volume":"11","author":"Sultana","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1021\/acs.jnatprod.9b01285","article-title":"Natural products as sources of new drugs over the nearly four decades from 01\/1981 to 09\/2019","volume":"83","author":"Newman","year":"2020","journal-title":"J. Nat. Prod."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"173759","DOI":"10.1016\/j.ejphar.2020.173759","article-title":"Flavonols as potential antiviral drugs targeting SARS-CoV-2 proteases (3CLpro and PLpro), spike protein, RNA-dependent RNA polymerase (RdRp) and angiotensin-converting enzyme II receptor (ACE2)","volume":"891","author":"Mouffouk","year":"2021","journal-title":"Eur. J. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1017\/jns.2016.41","article-title":"Flavonoids: An overview","volume":"5","author":"Panche","year":"2016","journal-title":"J. Nutr. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zaragoz\u00e1, C., Villaescusa, L., Monserrat, J., Zaragoz\u00e1, F., and \u00c1lvarez-Mon, M. (2020). Potential therapeutic anti-inflammatory and immunomodulatory effects of dihydroflavones, flavones, and flavonols. Molecules, 25.","DOI":"10.3390\/molecules25041017"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Kaul, R., Paul, P., Kumar, S., B\u00fcsselberg, D., Dwivedi, V.D., and Chaari, A. (2021). Promising antiviral activities of natural flavonoids against SARS-CoV-2 targets: Systematic review. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222011069"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"15452","DOI":"10.1038\/s41598-021-94951-6","article-title":"Comprehensive virtual screening of 4.8 k flavonoids reveals novel insights into allosteric inhibition of SARS-CoV-2 MPRO","volume":"11","author":"Sheen","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Godinho, P.I.C., Soengas, R.G., and Silva, V.L.M. (2021). Therapeutic potential of glycosyl flavonoids as anti-coronaviral agents. Pharmaceuticals, 14.","DOI":"10.3390\/ph14060546"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1093\/cid\/ciaa410","article-title":"Comparative replication and immune activation profiles of SARS-CoV-2 and SARS-CoV in human lungs: An ex vivo study with implications for the pathogenesis of COVID-19","volume":"71","author":"Chu","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e14","DOI":"10.1016\/S2666-5247(20)30004-5","article-title":"Comparative tropism, replication kinetics, and cell damage profiling of SARS-CoV-2 and SARS-CoV with implications for clinical manifestations, transmissibility, and laboratory studies of COVID-19: An observational study","volume":"1","author":"Chu","year":"2020","journal-title":"Lancet Microbe"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1038\/s41420-021-00428-w","article-title":"SARS-CoV-2 engages inflammasome and pyroptosis in human primary monocytes","volume":"7","author":"Ferreira","year":"2021","journal-title":"Cell Death Discov."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"111430","DOI":"10.1016\/j.biopha.2021.111430","article-title":"Flavonoids against the SARS-CoV-2 induced inflammatory storm","volume":"138","author":"Liskova","year":"2021","journal-title":"Biom. Pharmacot."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/s11101-021-09759-z","article-title":"Flavonoids are promising safe therapy against COVID-19","volume":"21","author":"Alzaabi","year":"2022","journal-title":"Phytochem. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e77","DOI":"10.1002\/cpcy.77","article-title":"Practical guidelines for collection, manipulation and inactivation of SARS-CoV-2 and COVID-19 clinical specimens","volume":"93","author":"Bain","year":"2020","journal-title":"Curr. Protoc. Cytom."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Chaves, O.A., Sacramento, C.Q., Ferreira, A.C., Mattos, M., Fintelman-Rodrigues, N., Temerozo, J.R., Vazquez, L., Pinto, D.P., da Silveira, G.P.E., and da Fonseca, L.B. (2022). Atazanavir is a competitive inhibitor of SARS-CoV-2 Mpro, impairing variants replication in vitro and in vivo. Pharmaceuticals, 15.","DOI":"10.3390\/ph15010021"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Sacramento, C.Q., Fintelman-Rodrigues, N., Dias, S.S.G., Temerozo, J.R., Da Silva, A.d.P.D., da Silva, C.S., Blanco, C., Ferreira, A.C., Mattos, M., and Soares, V.C. (2022). Unlike chloroquine, mefloquine inhibits SARS-CoV-2 infection in physiologically relevant cells. Viruses, 14.","DOI":"10.3390\/v14020374"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"9436","DOI":"10.1073\/pnas.1508686112","article-title":"Structural basis and functional analysis of the SARS coronavirus nsp14\u2013nsp10 complex","volume":"112","author":"Ma","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1002\/j.1460-2075.1991.tb07917.x","article-title":"Structural basis for the 3\u2032-5\u2032 exonuclease activity of Escherichia coli DNA polymerase I: A two metal ion mechanism","volume":"10","author":"Beese","year":"1991","journal-title":"EMBO J."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Chaves, O.A., Sacramento, C.Q., Fintelman-Rodrigues, N., Temerozo, J.R., Pereira-Dutra, F., Mizurini, D.M., Monteiro, R.Q., Vazquez, L., Bozza, P.T., and Castro-Faria-Neto, H.C. (2022). Apixaban, an orally available anticoagulant, inhibits SARS-CoV-2 replication and its major protease in a non-competitive way. J. Mol. Cell Biol., mjac039.","DOI":"10.1093\/jmcb\/mjac039"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4082","DOI":"10.1021\/acs.jcim.1c00258","article-title":"Pharmacophore model for SARS-CoV-2 3CLpro small-molecule inhibitors and in vitro experimental validation of computationally screened inhibitors","volume":"61","author":"Glaab","year":"2021","journal-title":"J. Chem. Inf. Model."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1038\/s41422-020-0356-z","article-title":"Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease","volume":"30","author":"Ma","year":"2020","journal-title":"Cell Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/s41422-020-00444-y","article-title":"Rational development of a human antibody cocktail that deploys multiple functions to confer Pan-SARS-CoVs protection","volume":"31","author":"Yao","year":"2021","journal-title":"Cell Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"393","DOI":"10.4155\/fmc-2021-0269","article-title":"Design of SARS-CoV-2 Mpro, PLpro dual-target inhibitors based on deep reinforcement learning and virtual screening","volume":"14","author":"Zhang","year":"2022","journal-title":"Future Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1002\/prot.26164","article-title":"Repurposing of FDA-approved drugs against active site and potential allosteric drug-binding sites of COVID-19 main protease","volume":"89","author":"Yuce","year":"2021","journal-title":"Proteins"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"23544","DOI":"10.1002\/anie.202010316","article-title":"Allosteric inhibition of the SARS-CoV-2 main protease: Insights from mass spectrometry based assays","volume":"59","author":"Lutomski","year":"2020","journal-title":"Angew. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/s41579-021-00586-9","article-title":"Structure and function of retroviral integrase","volume":"20","author":"Maertens","year":"2022","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3146","DOI":"10.1016\/j.bmc.2014.04.016","article-title":"Design and discovery of flavonoid-based HIV-1 integrase inhibitors targeting both the active site and the interaction with LEDGF\/p75","volume":"22","author":"Li","year":"2014","journal-title":"Bioorg. Med. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Gundertofte, K., and J\u00f8rgensen, F.S. (2000). Prediction of activity for a set of flavonoids against HIV-1 integrase. Molecular Modeling and Prediction of Bioactivity, Springer. [1st ed.].","DOI":"10.1007\/978-1-4615-4141-7"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1016\/j.sjbs.2016.01.004","article-title":"Extreme effects of Seabuckthorn extracts on influenza viruses and human cancer cells and correlation between flavonol glycosides and biological activities of extracts","volume":"24","author":"Enkhtaivan","year":"2017","journal-title":"Saudi J. Biol. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1067\/mai.2003.1456","article-title":"Fisetin, a flavonol, inhibits TH2-type cytokine production by activated human basophils","volume":"111","author":"Higa","year":"2003","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"647693","DOI":"10.3389\/fmicb.2021.647693","article-title":"Combining SARS-CoV-2 proofreading exonuclease and RNA-dependente RNA polymerase inhibitors as a strategy to combat COVID-19: A high-throughput in silico screening","volume":"12","author":"Khater","year":"2021","journal-title":"Front. Microbiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41573-020-00114-z","article-title":"Natural products in drug discovery: Advances and opportunities","volume":"20","author":"Atanazov","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_45","unstructured":"(2022, June 28). Pfizer\u2019s Novel COVID-19 Oral Antiviral Treatment Candidate Reduced Risk of Hospitalization or Death by 89% in Interim Analysis of Phase 2\/3 Epic-HR Study. Available online: https:\/\/www.pfizer.com\/news\/press-release\/press-release-detail\/pfizers-novel-COVID-19-oral-antiviral-treatment-candidate."},{"key":"ref_46","unstructured":"(2022, June 28). Do You Know All 17 SDGs?. Available online: https:\/\/sdgs.un.org\/goals."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/7\/1458\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:41:28Z","timestamp":1760139688000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/7\/1458"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,30]]},"references-count":46,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["v14071458"],"URL":"https:\/\/doi.org\/10.3390\/v14071458","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,30]]}}}