Wang Yining, Li Pengfei, Xu Lei, de Vries Annemarie C, Rottier Robbert J, Wang Wenshi, Crombag Marie-Rose B S, Peppelenbosch Maikel P, Kainov Denis E, Pan Qiuwei
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.
iScience. 2023 Aug 16;26(9):107631. doi: 10.1016/j.isci.2023.107631. eCollection 2023 Sep 15.
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.
冠状病毒严重感染常伴有过度炎症反应，需要采取治疗策略同时应对病毒和炎症。通过筛选对人体安全的广谱抗病毒药物库，我们发现吲哚美辛可在人细胞和气道类器官模型中抑制泛冠状病毒感染。将吲哚美辛与已获批准用于治疗COVID-19的口服抗病毒药物联合使用可产生协同抗冠状病毒活性。巧合的是，对美国食品药品监督管理局（FDA）批准的药物库进行筛选时，发现吲哚美辛是通过增加信号转导和转录激活因子1（STAT1）磷酸化而成为最有效的干扰素反应增强剂。将吲哚美辛与α干扰素联合使用对多种冠状病毒产生了协同抗病毒作用。吲哚美辛的抗冠状病毒活性与激活干扰素反应有关。在肺上皮细胞与巨噬细胞的共培养系统中，吲哚美辛可抑制病毒复制和炎症反应。总体而言，吲哚美辛是一种泛冠状病毒抑制剂，可同时抑制病毒引发的炎症反应。将吲哚美辛与口服抗病毒药物或α干扰素联合使用可进一步增强其治疗潜力。
