Natural Flavonoid Derivatives Have Pan-Coronavirus Antiviral Activity

first_pagesettingsOrder Article Reprints This is an early access version, the complete PDF, HTML, and XML versions will be available soon. Open AccessArticle Natural Flavonoid Derivatives Have Pan-Coronavirus Antiviral Activity by Mattia Mori 1,†ORCID,Deborah Quaglio 2,†,Andrea Calcaterra 2ORCID,Francesca Ghirga 2ORCID,Leonardo Sorrentino 3ORCID,Silvia Cammarone 2ORCID,Matteo Fracella 3ORCID,Alessandra D'Auria 3ORCID,Federica Frasca 3,Elena Criscuolo 4ORCID,Nicola Clementi 4,5ORCID,Nicasio Mancini 4,5,Bruno Botta 2ORCID,Guido Antonelli 3,Alessandra Pierangeli 3,‡ORCID andCarolina Scagnolari 3,*,‡ORCID 1 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy 2 Department of Chemistry and Technologies of Drugs, Sapienza University of Rome, 00185 Rome, Italy 3 Laboratory of Virology, Department of Molecular Medicine, Sapienza University of Rome, 00185 Rome, Italy 4 Laboratory of Medical Microbiology and Virology, Vita-Salute San Raffaele University, 20132 Milan, Italy 5 Laboratory of Medical Microbiology and Virology, IRCCS San Raffaele Hospital, 20132 Milan, Italy * Author to whom correspondence should be addressed. † These authors contributed equally to this work. ‡ These authors contributed equally to this work. Microorganisms 2023, 11(2), 314; https://doi.org/10.3390/microorganisms11020314 Received: 27 December 2022 / Revised: 17 January 2023 / Accepted: 18 January 2023 / Published: 25 January 2023 (This article belongs to the Special Issue 10th Anniversary of Microorganisms: Past, Present and Future) Download Versions Notes Abstract The SARS-CoV-2 protease (3CLpro) is one of the key targets for the development of efficacious drugs for COVID-19 treatment due to its essential role in the life cycle of the virus and exhibits high conservation among coronaviruses. Recent studies have shown that flavonoids, which are small natural molecules, have antiviral activity against coronaviruses (CoVs), including SARS-CoV-2. In this study, we identified the docking sites and binding affinity of several natural compounds, similar to flavonoids, and investigated their inhibitory activity towards 3CLpro enzymatic activity. The selected compounds were then tested in vitro for their cytotoxicity, for antiviral activity against SARS-CoV-2, and the replication of other coronaviruses in different cell lines. Our results showed that Baicalein (100 mg/mL) exerted strong 3CLpro activity inhibition (>90%), whereas Hispidulin and Morin displayed partial inhibition. Moreover, Baicalein, up to 25 mg/mL, hindered >50% of SARS-CoV-2 replication in Vero E6 cultures. Lastly, Baicalein displayed antiviral activity against alphacoronavirus (Feline-CoV) and betacoronavirus (Bovine-CoV and HCoV-OC43) in the cell lines. Our study confirmed the antiviral activity of Baicalein against SARS-CoV-2 and demonstrated clear evidence of its pan-coronaviral activity.