TY - JOUR T1 - Large scale screening discovers clofoctol as an inhibitor of SARS-CoV-2 replication that reduces COVID-19-like pathology JF - bioRxiv DO - 10.1101/2021.06.30.450483 SP - 2021.06.30.450483 AU - Sandrine Belouzard AU - Arnaud Machelart AU - Valentin Sencio AU - Thibaut Vausselin AU - Eik Hoffmann AU - Nathalie Deboosere AU - Yves Rouillé AU - Lowiese Desmarets AU - Karin Séron AU - Adeline Danneels AU - Cyril Robil AU - Loïc Belloy AU - Camille Moreau AU - Catherine Piveteau AU - Alexandre Biela AU - Alexandre Vandeputte AU - Séverine Heumel AU - Lucie Deruyter AU - Julie Dumont AU - Florence Leroux AU - Ilka Engelmann AU - Enagnon Kazali Alidjinou AU - Didier Hober AU - Priscille Brodin AU - Terence Beghyn AU - François Trottein AU - Benoît Déprez AU - Jean Dubuisson Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/06/30/2021.06.30.450483.abstract N2 - The fastest way to implement a treatment against a new rapidly emerging viral disease consists in screening the potential antiviral activity of drugs approved for human use. This has the advantage of shortening regulatory preclinical development steps. Here, we screened a library of drug compounds, already registered in one or several geographical areas, to identify those exhibiting antiviral activity against SARS-CoV-2 with relevant potency. Of the 1,942 compounds tested, 21 exhibited a substantial antiviral activity in Vero-81 cells. Among them, clofoctol, an antibacterial drug used for the treatment of bacterial respiratory tract infections, was further investigated due to its favorable safety profile and its pharmacokinetic properties. Notably, the peak concentration of clofoctol that can be achieved in human lungs is more than 20 times higher than its IC95 measured against SARS-CoV-2 in human pulmonary cells. Mechanistically, this compound inhibits SARS-CoV-2 at a post-entry step by specifically blocking translation initiation of viral RNA. Lastly, therapeutic treatment of human ACE2 receptor transgenic mice decreased viral load, reduced inflammatory gene expression and improved pulmonary pathology. Altogether, these data strongly support clofoctol as a therapeutic candidate for the treatment of COVID-19 patients.Competing Interest StatementT.B., L.B., C.M., S.B., P.B., N.D., B.D., Je.D., E.H., A.M., Y.R., T.V. are inventors on a patent application on repurposed antiviral activity of clofoctol against SARS-CoV-2 owned by Univ Lille, CNRS, INSERM, CHU Lille and Institut Pasteur de Lille. European Patent Application Serial No. EP20305633.8, entitled Compound and method for the treatment of coronaviruses, relates to this work and was filed on 10 June 2020. The Institut Pasteur de Lille received a financial support from the group LVMH to help launching a clinical trial with clofoctol ER -