There is an urgent need for specific antiviral treatments directed against SARS-CoV-2 to prevent the most severe forms of COVID-19. By drug repurposing, affordable therapeutics could be supplied worldwide in the present pandemic context. Targeting the nucleoprotein N of the SARS-CoV-2 coronavirus could be a strategy to impede viral replication and possibly other essential functions associated with viral N. The antiviral properties of naproxen, a non-steroidal anti-inflammatory drug (NSAID) that was previously demonstrated to be active against Influenza A virus, were evaluated against SARS-CoV-2. Intrinsic fluorescence spectroscopy, fluorescence anisotropy, and dynamic light scattering assays demonstrated naproxen binding to the nucleoprotein of SARS-Cov-2 as predicted by molecular modeling. Naproxen impeded recombinant N oligomerization and inhibited viral replication in infected cells. In VeroE6 cells and reconstituted human primary respiratory epithelium models of SARS-CoV-2 infection, naproxen specifically inhibited viral replication and protected the bronchial epithelia against SARS-CoV-2-induced damage. No inhibition of viral replication was observed with paracetamol or the COX-2 inhibitor celecoxib. Thus, among the NSAID tested, only naproxen combined antiviral and anti-inflammatory properties. Naproxen addition to the standard of care could be beneficial in a clinical setting, as tested in an ongoing clinical study.

Cancer Biology and Therapeutics Team INSERM UMR_S 938 Centre de Recherche Saint Antoine Sorbonne Universitè F 75012 Paris France

CIRI Centre International de Recherche en Infectiologie Univ Lyon Inserm U1111 Université Claude Bernard Lyon 1 CNRS UMR5308 ENS de Lyon F 69007 Lyon France

Department of Endocrinology AP HP Saint Antoine Hospital Institut Hospitalo Universitaire de Cardio métabolisme et Nutrition CRMR PRISIS F 75012 Paris France

Genetic and acquired lipodystrophies Team INSERM UMR_S 938 Centre de Recherche Saint Antoine Sorbonne Université F 75012 Paris France

INSERM UMR_S 938 Centre de Recherche Saint Antoine Sorbonne University and Department of Rheumatology AP HP Saint Antoine Hospital F 75012 Paris France

Institut Universitaire de France F 75231 Paris France

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences 11720 Prague Czech Republic

ISM UMR CNRS 5255 Université de Bordeaux F 33405 Talence France

Laboratoire de Biologie Computationnelle et Quantitative Institut de Biologie Paris Seine UMR CNRS 7238 Sorbonne Université F 75005 Paris France

Service d'Urgences SAMU SMUR Hôpital Avicenne AP HP F 93000 Bobigny France

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