The crystal structure of coronavirus RBD-TMPRSS2 complex provides basis for the discovery of therapeutic antibodies
Abstract 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....
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| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62023-2 |
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| Summary: | Abstract 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. |
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| ISSN: | 2041-1723 |