tetano
Editor, Senior Moderator
Nat Commun
. 2025 Jul 16;16(1):6541.
doi: 10.1038/s41467-025-60832-z. An orally available M[SUP]pro[/SUP]/TMPRSS2 bispecific inhibitor with potent anti-coronavirus efficacy in vivo
Huiping Shuai[SUP] #[/SUP][SUP] 1 [/SUP], Jingxin Qiao[SUP] #[/SUP][SUP] 2 [/SUP], Chaemin Yoon[SUP] #[/SUP][SUP] 1 [/SUP], Guo Zhang[SUP] #[/SUP][SUP] 2 [/SUP], Yuxin Hou[SUP] #[/SUP][SUP] 3 4 [/SUP], Xiaoyan Xia[SUP] #[/SUP][SUP] 2 [/SUP], Lei Wang[SUP] #[/SUP][SUP] 1 [/SUP], Xinyue Deng[SUP] #[/SUP][SUP] 2 [/SUP], Yifei Wang[SUP] 2 [/SUP], Qingquan Li[SUP] 5 6 [/SUP], Lianzhao Du[SUP] 1 [/SUP], Yuanchen Liu[SUP] 1 [/SUP], Minmin Zhou[SUP] 1 [/SUP], Hoi Ting Wong[SUP] 1 [/SUP], Jiaheng Hu[SUP] 1 [/SUP], Huan Liu[SUP] 1 [/SUP], Bingjie Hu[SUP] 1 [/SUP], Dong Wang[SUP] 7 [/SUP], Jingyi Su[SUP] 8 [/SUP], Yuying Pan[SUP] 8 [/SUP], Yongtao Ye[SUP] 9 [/SUP], Yan Chen[SUP] 2 [/SUP], Zhen Fang[SUP] 2 [/SUP], Ziyi Xia[SUP] 2 [/SUP], Yue Chai[SUP] 1 [/SUP], Jialu Shi[SUP] 1 [/SUP], Yang Wang[SUP] 1 [/SUP], Tianrenzheng Zhu[SUP] 1 [/SUP], Honglei Zhang[SUP] 1 10 [/SUP], Shuofeng Yuan[SUP] 1 11 12 [/SUP], Jie Zhou[SUP] 1 11 [/SUP], Jasper Fuk-Woo Chan[SUP] 1 3 11 12 13 14 [/SUP], Kwok-Yung Yuen[SUP] 1 3 11 12 13 14 [/SUP], Chunfu Xu[SUP] 5 6 [/SUP], Jian Lei[SUP] 15 [/SUP], Shengyong Yang[SUP] 16 [/SUP], Hin Chu[SUP] 17 18 19 20 [/SUP]
Affiliations
Coronaviruses have caused three major endemics in the past two decades. Alarmingly, recent identification of novel zoonotic coronaviruses that caused human infections suggests the risk of future coronavirus outbreak caused by spillover infection from animal reservoirs remains high. Therefore, development of alternative therapeutic options with broad-spectrum anti-coronavirus activities are urgently needed. Here, we develop an orally available bispecific inhibitor, TMP1, which simultaneously targets key coronavirus replication protease M[SUP]pro[/SUP] and the essential airway protease TMPRSS2. TMP1 shows broad-spectrum protection not only against different SARS-CoV-2 variants but also against multiple human-pathogenic coronaviruses in vitro. By using the K18-hACE2 transgenic mouse, hDPP4 knock-in mouse and golden Syrian hamster models, we demonstrate TMP1 cross-protects against highly-pathogenic coronaviruses (SARS-CoV-1, SARS-CoV-2 and MERS-CoV) in vivo and efficiently abrogates SARS-CoV-2 transmission. Through structural and mutagenesis studies, we confirm the direct interaction of TMP1 with M[SUP]pro[/SUP] and TMPRSS2, and pinpoint the key sites of interactions. Importantly, TMP1 inhibits the infection of nirmatrelvir-resistant SARS-CoV-2 escape mutants. Together, our findings demonstrate the antiviral potential of the bispecific M[SUP]pro[/SUP]/TMPRSS2 antiviral design against human-pathogenic coronaviruses and other emerging coronaviruses.
. 2025 Jul 16;16(1):6541.
doi: 10.1038/s41467-025-60832-z. An orally available M[SUP]pro[/SUP]/TMPRSS2 bispecific inhibitor with potent anti-coronavirus efficacy in vivo
Huiping Shuai[SUP] #[/SUP][SUP] 1 [/SUP], Jingxin Qiao[SUP] #[/SUP][SUP] 2 [/SUP], Chaemin Yoon[SUP] #[/SUP][SUP] 1 [/SUP], Guo Zhang[SUP] #[/SUP][SUP] 2 [/SUP], Yuxin Hou[SUP] #[/SUP][SUP] 3 4 [/SUP], Xiaoyan Xia[SUP] #[/SUP][SUP] 2 [/SUP], Lei Wang[SUP] #[/SUP][SUP] 1 [/SUP], Xinyue Deng[SUP] #[/SUP][SUP] 2 [/SUP], Yifei Wang[SUP] 2 [/SUP], Qingquan Li[SUP] 5 6 [/SUP], Lianzhao Du[SUP] 1 [/SUP], Yuanchen Liu[SUP] 1 [/SUP], Minmin Zhou[SUP] 1 [/SUP], Hoi Ting Wong[SUP] 1 [/SUP], Jiaheng Hu[SUP] 1 [/SUP], Huan Liu[SUP] 1 [/SUP], Bingjie Hu[SUP] 1 [/SUP], Dong Wang[SUP] 7 [/SUP], Jingyi Su[SUP] 8 [/SUP], Yuying Pan[SUP] 8 [/SUP], Yongtao Ye[SUP] 9 [/SUP], Yan Chen[SUP] 2 [/SUP], Zhen Fang[SUP] 2 [/SUP], Ziyi Xia[SUP] 2 [/SUP], Yue Chai[SUP] 1 [/SUP], Jialu Shi[SUP] 1 [/SUP], Yang Wang[SUP] 1 [/SUP], Tianrenzheng Zhu[SUP] 1 [/SUP], Honglei Zhang[SUP] 1 10 [/SUP], Shuofeng Yuan[SUP] 1 11 12 [/SUP], Jie Zhou[SUP] 1 11 [/SUP], Jasper Fuk-Woo Chan[SUP] 1 3 11 12 13 14 [/SUP], Kwok-Yung Yuen[SUP] 1 3 11 12 13 14 [/SUP], Chunfu Xu[SUP] 5 6 [/SUP], Jian Lei[SUP] 15 [/SUP], Shengyong Yang[SUP] 16 [/SUP], Hin Chu[SUP] 17 18 19 20 [/SUP]
Affiliations
- PMID: 40670362
- DOI: 10.1038/s41467-025-60832-z
Coronaviruses have caused three major endemics in the past two decades. Alarmingly, recent identification of novel zoonotic coronaviruses that caused human infections suggests the risk of future coronavirus outbreak caused by spillover infection from animal reservoirs remains high. Therefore, development of alternative therapeutic options with broad-spectrum anti-coronavirus activities are urgently needed. Here, we develop an orally available bispecific inhibitor, TMP1, which simultaneously targets key coronavirus replication protease M[SUP]pro[/SUP] and the essential airway protease TMPRSS2. TMP1 shows broad-spectrum protection not only against different SARS-CoV-2 variants but also against multiple human-pathogenic coronaviruses in vitro. By using the K18-hACE2 transgenic mouse, hDPP4 knock-in mouse and golden Syrian hamster models, we demonstrate TMP1 cross-protects against highly-pathogenic coronaviruses (SARS-CoV-1, SARS-CoV-2 and MERS-CoV) in vivo and efficiently abrogates SARS-CoV-2 transmission. Through structural and mutagenesis studies, we confirm the direct interaction of TMP1 with M[SUP]pro[/SUP] and TMPRSS2, and pinpoint the key sites of interactions. Importantly, TMP1 inhibits the infection of nirmatrelvir-resistant SARS-CoV-2 escape mutants. Together, our findings demonstrate the antiviral potential of the bispecific M[SUP]pro[/SUP]/TMPRSS2 antiviral design against human-pathogenic coronaviruses and other emerging coronaviruses.