tetano
Editor, Senior Moderator
Commun Biol
. 2025 Aug 1;8(1):1145.
doi: 10.1038/s42003-025-08570-2. The main protease (M[SUP]pro[/SUP]) from SARS-CoV-2 triggers plasma clotting in vitro by activating coagulation factors VII and FXII
Anna Pagotto[SUP] #[/SUP][SUP] 1 2 [/SUP], Federico Uliana[SUP] #[/SUP][SUP] 3 4 [/SUP], Elena Cavedon[SUP] 1 [/SUP], Giulia Nordio[SUP] 1 [/SUP], Andrea Pierangelini[SUP] 1 [/SUP], Laura Acquasaliente[SUP] 1 [/SUP], Maria Ludovica Macchia[SUP] 5 [/SUP], Massimo Bellanda[SUP] 5 [/SUP], Barbara Gatto[SUP] 1 [/SUP], Giustina De Silvestro[SUP] 6 [/SUP], Piero Marson[SUP] 6 [/SUP], Dario Gregori[SUP] 7 [/SUP], Paolo Simioni[SUP] 8 [/SUP], Paola Picotti[SUP] 2 [/SUP], Vincenzo De Filippis[SUP] 9 [/SUP]
Affiliations
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 (M[SUP]pro[/SUP]) can play a direct role in the activation of coagulation. Adding M[SUP]pro[/SUP] to human plasma increased clotting probability by 3-fold. Enzymatic assays and degradomics analysis indicate that M[SUP]pro[/SUP] cleaves and activates coagulation factors VII and XII. This activity is compatible with an extended secondary specificity of M[SUP]pro[/SUP] for R↓X that diverge from its well-established preference for LQ↓X. This finding is supported by HDX-MS characterization of the M[SUP]pro[/SUP] complex with an Arg-containing inhibitor, as well as the proteolytic cleavage of the peptide FTRLR↓SLEN by M[SUP]pro[/SUP]. Overall, integrating biochemical, proteomics and structural biology experiments, we unveil a novel mechanism linking SARS-CoV-2 infection to thrombotic complications in COVID-19.
. 2025 Aug 1;8(1):1145.
doi: 10.1038/s42003-025-08570-2. The main protease (M[SUP]pro[/SUP]) from SARS-CoV-2 triggers plasma clotting in vitro by activating coagulation factors VII and FXII
Anna Pagotto[SUP] #[/SUP][SUP] 1 2 [/SUP], Federico Uliana[SUP] #[/SUP][SUP] 3 4 [/SUP], Elena Cavedon[SUP] 1 [/SUP], Giulia Nordio[SUP] 1 [/SUP], Andrea Pierangelini[SUP] 1 [/SUP], Laura Acquasaliente[SUP] 1 [/SUP], Maria Ludovica Macchia[SUP] 5 [/SUP], Massimo Bellanda[SUP] 5 [/SUP], Barbara Gatto[SUP] 1 [/SUP], Giustina De Silvestro[SUP] 6 [/SUP], Piero Marson[SUP] 6 [/SUP], Dario Gregori[SUP] 7 [/SUP], Paolo Simioni[SUP] 8 [/SUP], Paola Picotti[SUP] 2 [/SUP], Vincenzo De Filippis[SUP] 9 [/SUP]
Affiliations
- PMID: 40750828
- PMCID: PMC12316959
- DOI: 10.1038/s42003-025-08570-2
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 (M[SUP]pro[/SUP]) can play a direct role in the activation of coagulation. Adding M[SUP]pro[/SUP] to human plasma increased clotting probability by 3-fold. Enzymatic assays and degradomics analysis indicate that M[SUP]pro[/SUP] cleaves and activates coagulation factors VII and XII. This activity is compatible with an extended secondary specificity of M[SUP]pro[/SUP] for R↓X that diverge from its well-established preference for LQ↓X. This finding is supported by HDX-MS characterization of the M[SUP]pro[/SUP] complex with an Arg-containing inhibitor, as well as the proteolytic cleavage of the peptide FTRLR↓SLEN by M[SUP]pro[/SUP]. Overall, integrating biochemical, proteomics and structural biology experiments, we unveil a novel mechanism linking SARS-CoV-2 infection to thrombotic complications in COVID-19.