Scholarlink

<p>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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

The main protease (Mpro) from SARS-CoV-2 triggers plasma clotting in vitro by activating coagulation factors VII and FXII

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月1日

查看全文
  • Anna Pagotto,
  • Federico Uliana,
  • Elena Cavedon,
  • Giulia Nordio,
  • Andrea Pierangelini,
  • Laura Acquasaliente,
  • Maria Ludovica Macchia,
  • Massimo Bellanda,
  • Barbara Gatto,
  • Giustina De Silvestro,
  • Piero Marson,
  • Dario Gregori,
  • Paolo Simioni,
  • Paola Picotti,
  • Vincenzo De Filippis

摘要

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.