An orally available Mpro/TMPRSS2 bispecific inhibitor with potent anti-coronavirus efficacy in vivo

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.

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Publication Details

Journal
Nature Communications
Published
2025-07-16
DOI
https://doi.org/10.1038/s41467-025-60832-z
Citations
4
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
Field-Weighted Citation Impact
5.58

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article

An orally available Mpro/TMPRSS2 bispecific inhibitor with potent anti-coronavirus efficacy in vivo

Jie Zhou, Xinyue Deng, Hoi Ting Wong, Ziyi Xia et al.
4 citations
Nature Communications
SARS-CoV-2 and COVID-19 Research
5.58
article

An orally available Mpro/TMPRSS2 bispecific inhibitor with potent anti-coronavirus efficacy in vivo

Jie Zhou, Xinyue Deng, Hoi Ting Wong, Ziyi Xia, Xiaoyan Xia, Chaemin Yoon, Yang Wang, Yue Chai, Shuofeng Yuan, Tianrenzheng Zhu, Bingjie Hu, Jiaheng Hu, Yongtao Ye, Huiping Shuai, Huan Liu, Hin Chu, Jasper Fuk‐Woo Chan, Minmin Zhou, Yuxin Hou, Shengyong Yang, Jian Lei, Yuanchen Liu, Kwok‐Yung Yuen, Jialu Shi, Chunfu Xu, Yuying Pan, Yifei Wang, Dong Wang, Wenxin Wang, Guo Zhang, Honglei Zhang, Yan Chen, Qingquan Li, Jingxin Qiao, Zhen Fang, Lianzhao Du, Jingyi Su
article en
4 citations

Abstract

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.

Nature CommunicationsVol. 16(1)
Department of Health (CN), Sichuan University (CN), Queen Mary Hospital (CN), Hong Kong Science and Technology Parks Corporation (HK), National Institute of Biological Sciences, Beijing (CN), Guangzhou Experimental Station (CN), First Affiliated Hospital of Guangzhou Medical University (CN), University of Hong Kong - Shenzhen Hospital (CN), HKU-Pasteur Research Pole (HK), Institut de Recherche et d’Innovation (FR), State Key Laboratory of Respiratory Disease (CN), Henan Agricultural University (CN), Hainan Medical University (CN), University of Hong Kong (HK), Guangzhou Medical University (CN), Tsinghua University (CN)
National Science Foundation, National Natural Science Foundation of China, Innovation and Technology Commission, Sichuan University, Young Scientists Fund, Sanming Project of Medicine in Shenzhen, National Key Research and Development Program of China, West China Hospital, Sichuan University, National Cancer Institute
Good health and well-being
Openalex Percentile: Top 4%
SARS-CoV-2 and COVID-19 Research
5.58
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