Abstract: pathogens Article Bioactive Polyphenolic Compounds Showing Strong Antiviral Activities against Severe Acute Respiratory Syndrome Coronavirus 2 Ahmed Kandeil 1,† , Ahmed Mostafa 1,† , Omnia Kutkat 1 , Yassmin Moatasim 1 , Ahmed A. Al-Karmalawy 2 , Adel A. Rashad 3 , Ahmed E. Kayed 1 , Azza E. Kayed 4 , Rabeh El-Shesheny 1 , Ghazi Kayali 5,6, * and Mohamed A. Ali 1, * 1 2 3 4



 5 6 Citation: Kandeil, A.; Mostafa, A.; Kutkat, O.; Moatasim, Y.; * † Center of Scientific Excellence for Influenza Viruses, National Research Centre, Giza 12622, Egypt; Ahmed.Kandeil@human-link.org (A.K.); ahmed_elsayed@daad-alumni.de (A.M.); Omnia.Abdelaziz@human-link.org (O.K.); Yasmin.Moatasim@human-link.org (Y.M.); Ahmed.Elsayed@human-link.org (A.E.K.); ra_eny@yahoo.com (R.E.-S.) Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt; akarmalawy@horus.edu.eg Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA; aaa396@drexel.edu Radiation Biology Department, Atomic Energy Authority, Cairo 13759, Egypt; azzakaed60@gmail.com Department of Epidemiology, Human Genetics, and Environmental Sciences, University of Texas, Houston, TX 77030, USA Human Link, Jewellery & Gemplex, Dubai 48800, United Arab Emirates Correspondence: ghazi@human-link.org (G.K.); mohamedahmedali2004@yahoo.com (M.A.A.) Equally contributed as first author. Al-Karmalawy, A.A.; Rashad, A.A.; Kayed, A.E.; Kayed, A.E.; El-Shesheny, R.; Kayali, G.; et al. Bioactive Polyphenolic Compounds Showing Strong Antiviral Activities against Severe Acute Respiratory Syndrome Coronavirus 2. Pathogens 2021, 10, 758. https://doi.org/ 10.3390/pathogens10060758 Academic Editors: David J. Allen and Sonia Zuñiga Received: 24 March 2021 Accepted: 10 June 2021 Published: 15 June 2021 Publisher’s Note: MDPI stays neutral Abstract: Until now, there has been no direct evidence of the effectiveness of repurposed FDAapproved drugs against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infections. Although curcumin, hesperidin, and quercetin have broad spectra of pharmacological properties, their antiviral activities against SARS-CoV-2 remain unclear. Our study aimed to assess the in vitro antiviral activities of curcumin, hesperidin, and quercetin against SARS-CoV-2 compared to hydroxychloroquine and determine their mode of action. In Vero E6 cells, these compounds significantly inhibited virus replication, mainly as virucidal agents primarily indicating their potential activity at the early stage of viral infection. To investigate the mechanism of action of the tested compounds, molecular docking studies were carried out against both SARS-CoV-2 spike (S) and main protease (Mpro) receptors. Collectively, the obtained in silico and in vitro findings suggest that the compounds could be promising SARS-CoV-2 Mpro inhibitors. We recommend further preclinical and clinical studies on the studied compounds to find a potential therapeutic targeting COVID-19 in the near future. Keywords: SARS-CoV-2; COVID-19; antiviral; curcumin; hesperidin; quercetin; molecular docking with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license..