Abstract
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.
Highlights
The current pandemic of novel coronavirus disease 2019 (COVID-19) was caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the origin of which is not yet known, with first reported cases in Wuhan, Hubei province, China, in December 2019 [1,2]
We demonstrate here that the ability of naproxen to bind the nucleoprotein of SARS-CoV2 characterized by an IC50 of 1.1 μM to dimeric Nterminal domain (NTD) and stabilize N NTD against heat denaturation
Naproxen competed with RNA binding to N NTD, yielding a KD = 4.4 ± 1.4 μM using a monomeric NTD, and drastically decreased N oligomerization as shown by a combination of modeling, fluorescence anisotropy, thermal shift assay and Dynamic Light Scattering (DLS) data
Summary
The current pandemic of novel coronavirus disease 2019 (COVID-19) was caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the origin of which is not yet known, with first reported cases in Wuhan, Hubei province, China, in December 2019 [1,2]. SARS-CoV-2 is a beta-coronavirus closely related to the severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1) and the Middle East respiratory syndrome coronavirus (MERS-CoV), which emerged in 2003 and 2012, respectively. These viruses were transmitted from animals to humans and caused severe respiratory diseases in afflicted individuals. The exacerbated inflammatory response in severe COVID-19 cases presents similarity to the cytokine storm observed in severe cases of H5N1 Influenza virus infection and overall inflammation, as in the 1918 Influenza A pandemic [3]. We hypothesize that drugs combining anti-inflammatory and antiviral effects could even more efficiently reduce the symptoms of respiratory distress and inflammation caused by COVID-19 [5]
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