The main protease (Mpro) from SARS-CoV-2 triggers plasma clotting in vitro by activating coagulation factors VII and FXII
Abstract Although the connection between COVID-19 and coagulopathy has been clear since the beginning of SARS-CoV-2 pandemic, the underlying molecular mechanisms remain elusive. Available data support that the hyper-coagulant state is sustained by systemic inflammation. Here we show that the SARS-Co...
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| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-08-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08570-2 |
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| Summary: | Abstract Although the connection between COVID-19 and coagulopathy has been clear since the beginning of SARS-CoV-2 pandemic, the underlying molecular mechanisms remain elusive. Available data support that the hyper-coagulant state is sustained by systemic inflammation. Here we show that the SARS-CoV-2 main protease (Mpro) can play a direct role in the activation of coagulation. Adding Mpro to human plasma increased clotting probability by 3-fold. Enzymatic assays and degradomics analysis indicate that Mpro cleaves and activates coagulation factors VII and XII. This activity is compatible with an extended secondary specificity of Mpro for R↓X that diverge from its well-established preference for LQ↓X. This finding is supported by HDX-MS characterization of the Mpro complex with an Arg-containing inhibitor, as well as the proteolytic cleavage of the peptide FTRLR↓SLEN by Mpro. Overall, integrating biochemical, proteomics and structural biology experiments, we unveil a novel mechanism linking SARS-CoV-2 infection to thrombotic complications in COVID-19. |
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| ISSN: | 2399-3642 |