Discovery of SARS-CoV-2 PLpro inhibitors and RIPK1 inhibitors with synergistic antiviral efficacy in a mouse COVID-19 model

作者：Hengyue Shan, Yuzheng Zhou, Ying Qin, Taijie Guo, Xiao Zhang, Huaijiang Xiang, Qi He, Shi Chen, Dekang Li, Jingli Liu, Chunting Qi, Shi Chen, Jiajia Dong, Gang Xu, Ying Li, Zheng Zhang, Li Tan · 发表于：Acta Pharmaceutica Sinica B · 年份：2025 · DOI：10.1016/j.apsb.2025.09.026 · 被引用次数：4 · 研究领域：interferon and immune responses、SARS-CoV-2 and COVID-19 Research、Vitamin C and Antioxidants Research

SARS-CoV-2 continues to propagate globally, posing non-negligible risks of severe COVID-19. Although several clinical antivirals and immunosuppressants offer crucial protection, there is a persistent need for additional therapeutic options to counter emerging viral variants and drug resistances. New strategies focusing on host targets, or simultaneously suppressing viral replication and inflammation, particularly require rigorous validation. Compared to established antiviral targets, PLpro presents an alternative actionable vulnerability in SARS-CoV-2 infection. Meanwhile, RIPK1 was pinpointed to enhance both viral replication and the resulting cytokine storm in host cells. However, inhibitors targeting PLpro or RIPK1 require further optimization for preclinical studies, and their combined efficacy in vivo has yet to be explored. Here, we report the discoveries of potent and selective PLpro inhibitors and RIPK1 inhibitors through high-throughput approaches. Our lead compounds, SHY1643 and QY1892, demonstrated synergistic and robust effects in reducing the viral loads and cytokine release syndromes in SARS-CoV-2-infected mice. These findings establish a proof-of-concept combination therapy strategy for treating severe COVID-19, and provide promising leads for the clinical drug development.