Combating pan-coronavirus infection by indomethacin through simultaneously inhibiting viral replication and inflammatory response
Wang, Yining; Li, Pengfei; Xu, Lei; de Vries, Annemarie C.; Rottier, Robbert J.; Wang, Wenshi; Crombag, Marie-Rose B.S.; Peppelenbosch, Maikel P.; Kaynov, Denis; Pan, Qiuwei
Peer reviewed, Journal article
Published version
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https://hdl.handle.net/11250/3120400Utgivelsesdato
2023Metadata
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Sammendrag
Severe infections with coronaviruses are often accompanied with hyperinflammation, requiring therapeutic strategies to simultaneously tackle the virus and inflammation. By screening a safe-in-human broad-spectrum antiviral agents library, we identified that indomethacin can inhibit pan-coronavirus infection in human cell and airway organoids models. Combining indomethacin with oral antiviral drugs authorized for treating COVID-19 results in synergistic anti-coronavirus activity. Coincidentally, screening a library of FDA-approved drugs identified indomethacin as the most potent potentiator of interferon response through increasing STAT1 phosphorylation. Combining indomethacin with interferon-alpha exerted synergistic antiviral effects against multiple coronaviruses. The anti-coronavirus activity of indomethacin is associated with activating interferon response. In a co-culture system of lung epithelial cells with macrophages, indomethacin inhibited both viral replication and inflammatory response. Collectively, indomethacin is a pan-coronavirus inhibitor that can simultaneously inhibit virus-triggered inflammatory response. The therapeutic potential of indomethacin can be further augmented by combining it with oral antiviral drugs or interferon-alpha.