Large scale screening discovers clofoctol as an inhibitor of SARS-CoV-2 replication that reduces COVID-19-like pathology

Sandrine Belouzard (1) , Arnaud Machelart (1) , Valentin Sencio (1) , Thibaut Vausselin (1, 2) , Eik Hoffmann (1) , Nathalie Deboosere (1, 3) , Yves Rouillé (1) , Lowiese Desmarets (1) , Karin Séron (1) , Adeline Danneels (1) , Cyril Robil (1) , Loïc Belloy (2) , Camille Moreau (2) , Catherine Piveteau (4) , Alexandre Biela (4) , Alexandre Vandeputte (1, 3) , Séverine Heumel (1) , Lucie Deruyter (1) , Julie Dumont (3, 4) , Florence Leroux (4, 3) , Ilka Engelmann (5) , Enagnon Kazali Alidjinou (5) , Didier Hober (5) , Priscille Brodin (1, 3) , Terence Beghyn (2) , François Trottein (1) , Benoît Déprez (3, 4) , Jean Dubuisson (1)

1 CIIL - Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204
2 Apteeus [Lille]
3 PLBS - Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41
4 M2SV - Médicaments et molécules pour agir sur les Systèmes Vivants - U 1177
5 Laboratoire de Virologie - Laboratoire de Virologie - ULR 3610

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 IC 95 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.

Domaines: Virologie

Sandrine Belouzard, Arnaud Machelart, Valentin Sencio, Thibaut Vausselin, Eik Hoffmann, et al.. Large scale screening discovers clofoctol as an inhibitor of SARS-CoV-2 replication that reduces COVID-19-like pathology. 2021. ⟨hal-03357964⟩