An orally available Mpro/TMPRSS2 bispecific inhibitor with potent anti-coronavirus efficacy in vivo
Huiping Shuai,
Jingxin Qiao,
Chaemin Yoon,
Guo Zhang,
Yuxin Hou,
Xiaoyan Xia,
Lei Wang,
Xinyue Deng,
Yifei Wang,
Qingquan Li,
Lianzhao Du,
Yuanchen Liu,
Minmin Zhou,
Hoi Ting Wong,
Jiaheng Hu,
Huan Liu,
Bingjie Hu,
Dong Wang,
Jingyi Su,
Yuying Pan,
Yongtao Ye,
Yan Chen,
Zhen Fang,
Ziyi Xia,
Yue Chai,
Jialu Shi,
Yang Wang,
Tianrenzheng Zhu,
Honglei Zhang,
Shuofeng Yuan,
Jie Zhou,
Jasper Fuk-Woo Chan,
Kwok-Yung Yuen,
Chunfu Xu,
Jian Lei (),
Shengyong Yang () and
Hin Chu ()
Additional contact information
Huiping Shuai: State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, and Pandemics Research Alliance Unit at The University of Hong Kong
Jingxin Qiao: Sichuan University
Chaemin Yoon: State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, and Pandemics Research Alliance Unit at The University of Hong Kong
Guo Zhang: Sichuan University
Yuxin Hou: Guangzhou Laboratory
Xiaoyan Xia: Sichuan University
Lei Wang: State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, and Pandemics Research Alliance Unit at The University of Hong Kong
Xinyue Deng: Sichuan University
Yifei Wang: Sichuan University
Qingquan Li: National Institute of Biological Sciences
Lianzhao Du: State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, and Pandemics Research Alliance Unit at The University of Hong Kong
Yuanchen Liu: State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, and Pandemics Research Alliance Unit at The University of Hong Kong
Minmin Zhou: State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, and Pandemics Research Alliance Unit at The University of Hong Kong
Hoi Ting Wong: State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, and Pandemics Research Alliance Unit at The University of Hong Kong
Jiaheng Hu: State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, and Pandemics Research Alliance Unit at The University of Hong Kong
Huan Liu: State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, and Pandemics Research Alliance Unit at The University of Hong Kong
Bingjie Hu: State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, and Pandemics Research Alliance Unit at The University of Hong Kong
Dong Wang: Guangzhou Medical University
Jingyi Su: the First Affiliated Hospital of Guangzhou Medical University
Yuying Pan: the First Affiliated Hospital of Guangzhou Medical University
Yongtao Ye: The University of Hong Kong
Yan Chen: Sichuan University
Zhen Fang: Sichuan University
Ziyi Xia: Sichuan University
Yue Chai: State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, and Pandemics Research Alliance Unit at The University of Hong Kong
Jialu Shi: State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, and Pandemics Research Alliance Unit at The University of Hong Kong
Yang Wang: State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, and Pandemics Research Alliance Unit at The University of Hong Kong
Tianrenzheng Zhu: State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, and Pandemics Research Alliance Unit at The University of Hong Kong
Honglei Zhang: State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, and Pandemics Research Alliance Unit at The University of Hong Kong
Shuofeng Yuan: State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, and Pandemics Research Alliance Unit at The University of Hong Kong
Jie Zhou: State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, and Pandemics Research Alliance Unit at The University of Hong Kong
Jasper Fuk-Woo Chan: State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, and Pandemics Research Alliance Unit at The University of Hong Kong
Kwok-Yung Yuen: State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, and Pandemics Research Alliance Unit at The University of Hong Kong
Chunfu Xu: National Institute of Biological Sciences
Jian Lei: Sichuan University
Shengyong Yang: Sichuan University
Hin Chu: State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, and Pandemics Research Alliance Unit at The University of Hong Kong
Nature Communications, 2025, vol. 16, issue 1, 1-24
Abstract:
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 Mpro 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 Mpro 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 Mpro/TMPRSS2 antiviral design against human-pathogenic coronaviruses and other emerging coronaviruses.
Date: 2025
References: Add references at CitEc
Citations:
Downloads: (external link)
https://www.nature.com/articles/s41467-025-60832-z Abstract (text/html)
Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.
Export reference: BibTeX
RIS (EndNote, ProCite, RefMan)
HTML/Text
Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60832-z
Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/
DOI: 10.1038/s41467-025-60832-z
Access Statistics for this article
Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie
More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().