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
Affiliations
Yining Wang
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
Pengfei Li
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
Lei Xu
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands; 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
Annemarie C. de Vries
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
Robbert J. Rottier
Department of Pediatric Surgery, Erasmus MC-Sophia Children’s Hospital, Rotterdam, the Netherlands; Department of Cell Biology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
Wenshi Wang
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands; Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
Marie-Rose B.S. Crombag
Department of Hospital Pharmacy, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
Maikel P. Peppelenbosch
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
Denis E. Kainov
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7028 Trondheim, Norway; Institute of Technology, University of Tartu, 50090 Tartu, Estonia
Qiuwei Pan
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands; Corresponding author
Summary: 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.
