tetano
Editor, Senior Moderator
Nat Commun
. 2025 Jul 18;16(1):6636.
doi: 10.1038/s41467-025-62023-2. The crystal structure of coronavirus RBD-TMPRSS2 complex provides basis for the discovery of therapeutic antibodies
Zhuoqian Zhao[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Qi Yang[SUP] #[/SUP][SUP] 4 [/SUP], Xiaoce Liu[SUP] #[/SUP][SUP] 1 2 [/SUP], Mengfei Li[SUP] #[/SUP][SUP] 1 2 [/SUP], Yinkai Duan[SUP] #[/SUP][SUP] 1 2 [/SUP], Mingjuan Du[SUP] 1 [/SUP], Anqi Zhou[SUP] 4 [/SUP], Huanzhen Liu[SUP] 1 [/SUP], Yujia He[SUP] 1 2 [/SUP], Wei Wang[SUP] 1 [/SUP], Yuchi Lu[SUP] 1 2 3 [/SUP], Xiaoyu Zhang[SUP] 1 2 3 [/SUP], Haofeng Wang[SUP] 1 2 [/SUP], Xiuna Yang[SUP] 5 6 [/SUP], Hongkai Zhang[SUP] 7 8 [/SUP], Xinwen Chen[SUP] 9 [/SUP], Zihe Rao[SUP] 10 [/SUP], Haitao Yang[SUP] 11 12 [/SUP]
Affiliations
HCoV-HKU1, one of seven human coronaviruses (HCoVs) that have harmful effects on human health, accounts for a substantial portion of common cold cases and can cause severe respiratory diseases in certain populations. Currently, effective antiviral treatments against this virus are limited. Recently, TMPRSS2, a host protease long acknowledged for its role in priming the spike proteins of various CoVs and promoting viral entry, was identified as a functional receptor for HCoV-HKU1, opening an avenue for anti-HCoV-HKU1 therapy development. In this study, we elucidate the detailed molecular mechanism underlying the interaction between the HCoV-HKU1 receptor-binding domain (RBD) and TMPRSS2 via crystallography. Guided by these structural insights, we successfully develop two types of therapeutic antibodies against HCoV-HKU1. The first type neutralizes the RBD, potently disrupting its interaction with TMPRSS2 and preventing viral infection. The second type targets TMPRSS2, inhibiting its enzymatic activity and/or interfering with its binding to the RBD. The latter demonstrates broad-spectrum anti-CoV activity, as the enzymatic activity of TMPRSS2 is crucial for both HCoV-HKU1 infection and other CoV infections. Our findings provide crucial structural insights into the recognition of TMPRSS2 by HCoV-HKU1 and offer promising antibody-based strategies for combating HCoV-HKU1 and other CoV infections.
. 2025 Jul 18;16(1):6636.
doi: 10.1038/s41467-025-62023-2. The crystal structure of coronavirus RBD-TMPRSS2 complex provides basis for the discovery of therapeutic antibodies
Zhuoqian Zhao[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Qi Yang[SUP] #[/SUP][SUP] 4 [/SUP], Xiaoce Liu[SUP] #[/SUP][SUP] 1 2 [/SUP], Mengfei Li[SUP] #[/SUP][SUP] 1 2 [/SUP], Yinkai Duan[SUP] #[/SUP][SUP] 1 2 [/SUP], Mingjuan Du[SUP] 1 [/SUP], Anqi Zhou[SUP] 4 [/SUP], Huanzhen Liu[SUP] 1 [/SUP], Yujia He[SUP] 1 2 [/SUP], Wei Wang[SUP] 1 [/SUP], Yuchi Lu[SUP] 1 2 3 [/SUP], Xiaoyu Zhang[SUP] 1 2 3 [/SUP], Haofeng Wang[SUP] 1 2 [/SUP], Xiuna Yang[SUP] 5 6 [/SUP], Hongkai Zhang[SUP] 7 8 [/SUP], Xinwen Chen[SUP] 9 [/SUP], Zihe Rao[SUP] 10 [/SUP], Haitao Yang[SUP] 11 12 [/SUP]
Affiliations
- PMID: 40681508
- PMCID: PMC12274457
- DOI: 10.1038/s41467-025-62023-2
HCoV-HKU1, one of seven human coronaviruses (HCoVs) that have harmful effects on human health, accounts for a substantial portion of common cold cases and can cause severe respiratory diseases in certain populations. Currently, effective antiviral treatments against this virus are limited. Recently, TMPRSS2, a host protease long acknowledged for its role in priming the spike proteins of various CoVs and promoting viral entry, was identified as a functional receptor for HCoV-HKU1, opening an avenue for anti-HCoV-HKU1 therapy development. In this study, we elucidate the detailed molecular mechanism underlying the interaction between the HCoV-HKU1 receptor-binding domain (RBD) and TMPRSS2 via crystallography. Guided by these structural insights, we successfully develop two types of therapeutic antibodies against HCoV-HKU1. The first type neutralizes the RBD, potently disrupting its interaction with TMPRSS2 and preventing viral infection. The second type targets TMPRSS2, inhibiting its enzymatic activity and/or interfering with its binding to the RBD. The latter demonstrates broad-spectrum anti-CoV activity, as the enzymatic activity of TMPRSS2 is crucial for both HCoV-HKU1 infection and other CoV infections. Our findings provide crucial structural insights into the recognition of TMPRSS2 by HCoV-HKU1 and offer promising antibody-based strategies for combating HCoV-HKU1 and other CoV infections.