Combating pan-coronavirus infection by indomethacin through simultaneously inhibiting viral replication and inflammatory response

Yining Wang; Pengfei Li; Lei Xu; Annemarie C de Vries; Robbert J Rottier; Wenshi Wang; Marie-Rose B S Crombag; Maikel P Peppelenbosch; Denis E Kainov; Qiuwei Pan

doi:10.1016/j.isci.2023.107631

Combating pan-coronavirus infection by indomethacin through simultaneously inhibiting viral replication and inflammatory response

iScience. 2023 Aug 16;26(9):107631. doi: 10.1016/j.isci.2023.107631. eCollection 2023 Sep 15.

Authors

Yining Wang¹, Pengfei Li¹, Lei Xu^{1

2}, Annemarie C de Vries¹, Robbert J Rottier^{3

4}, Wenshi Wang^{1

5}, Marie-Rose B S Crombag⁶, Maikel P Peppelenbosch¹, Denis E Kainov^{7

8}, Qiuwei Pan¹

Affiliations

¹ Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
² State Key Laboratory of Crop Stress Biology for Arid Areas, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling 712100, Shaanxi, China.
³ Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.
⁴ Department of Cell Biology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
⁵ Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China.
⁶ Department of Hospital Pharmacy, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
⁷ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7028 Trondheim, Norway.
⁸ Institute of Technology, University of Tartu, 50090 Tartu, Estonia.

Abstract

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.

Keywords: Drugs; Immune response; Virology.