Antiviral Properties of the NSAID Drug Naproxen Targeting the Nucleoprotein of SARS-CoV-2 Coronavirus

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.

Identifying potential novel insights for COVID-19 pathogenesis and therapeutics using an integrated bioinformatics analysis of host transcriptome

“…Naproxen has antiviral and anti-inflammatory effects. It inhibted replication of SARS-CoV-2 and protected against virus-induced damage pulmonary epithelium in vitro [85] . Clinical trials were conducted to study the safety and efficacy of Fostamatinib, Acalabrutinib, Ibrutinib, and Bevacizumab, Alteplase, Aspirin, and Naproxen for hospitalized patients with COVID-19 ( ClinicalTrials.gov ) (NCT04579393-NCT04497948-NCT04375397-NCT04275414 -NCT04357730-NCT04365309- NCT04325633 ).…”

Potential inhibitors of the main protease of SARS-CoV-2 and modulators of arachidonic acid pathway: Non-steroidal anti-inflammatory drugs against COVID-19

“…Due to the severity of the global health pandemic caused by COVID-19, discovering the drugs capable of inhibiting SARS-CoV-2 can be considered as a therapeutic target in the COVID treatment. In this regard, repurposing FDA-approved drugs, such as NSAIDs against COVID-19, can provide therapeutic alternatives which can be used as an effective, safe treatment for COVID-19 [ 12 , 38 ].…”

“…Some recent papers have studied the antiviral activity of NSAIDs against SARS-CoV-2 protein. For example, they showed that the anti-viral activity of Ketotifen, Indomethacin, and Naproxen could reduce SARS-CoV-2 replication [ [10] , [11] , [12] ]. Furthermore, it was shown that indomethacin exerts anti-SARS-CoV activity in both in vivo and in vitro models [ 13 ].…”

Nonsteroidal anti-inflammatory drugs and glucocorticoids in COVID-19

“…Celecoxib, at concentrations not clinically achievable (50 microM), inhibits the main protease of SARS-CoV-2, M-pro, in vitro ( Gimeno et al, 2020 ), but the effect on viral entry or replication was not assessed. Naproxen prevented SARS-CoV-2 nucleoprotein oligomerization by binding its N-terminal domain and inhibited viral replication in VERO E6 cells and reconstituted human pulmonary epithelium ( Terrier et al, 2021 ). In silico analyses of publicly available transcriptomic databases of rat kidney tissues treated with multiple NSAIDs in vivo found modulated expression of receptors for SARS-CoV-2.…”