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 ...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.展开更多
基金supported by grants from the National Key R&D Program(2023YFC260630 to Li Tan,Gang Xu and Yuzheng Zhou,China)National Natural Science Foundation of China(82151212 to Zheng Zhang and Li Tan,and 32170755 to Ying Li)+3 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB1060000 to Li Tan)Shenzhen Science and Technology Program(JCYJ20220818103017036 to Zheng Zhang,China)Shanghai Basic Research Pioneer Project(Li Tan)Shanghai Municipal Science and Technology Major Project(Li Tan).
文摘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.
