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<p>The protease TMPRSS2 facilitates coronavirus infections, yet its mechanism of viral glycoprotein recognition remains unclear. Here we show that, following ACE2 engagement of the SARS-CoV-2 spike (S) inducing the early fusion intermediate conformation (E-FIC), TMPRSS2 cleaves the R815 S<sub>2</sub>′ site and promotes fusogenic conformational changes leading to viral entry. We unveil TMPRSS2 recognition of S<sub>2</sub>′, identify key residues modulating binding specificity and demonstrate that S<sub>2</sub>′ site-directed broadly neutralizing antibodies target E-FIC and inhibit viral entry by blocking TMPRSS2 access. We computationally designed stabilized E-FIC as a vaccine candidate, overcoming the transient nature of this state. We describe a TMPRSS2-directed monoclonal antibody inhibiting several coronaviruses, including SARS-CoV-2 variants and protecting mice against SARS-CoV-2 challenge. These results outline the mechanistic role of TMPRSS2 and S<sub>2</sub>′ site-directed antibodies in coronavirus entry.</p>

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TMPRSS2-mediated coronavirus spike activation and inhibition

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月28日

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  • Matthew McCallum,
  • James Brett Case,
  • Jack T. Brown,
  • Young-Jun Park,
  • Jimin Lee,
  • Emmajay Sutherland,
  • Anupriya Aggarwal,
  • Cecily Gibson,
  • Florian A. Lempp,
  • Cameron Stewart,
  • M. Alejandra Tortorici,
  • Shilpa Sanapala,
  • Jun Siong Low,
  • Daniel Asarnow,
  • Dana Bohan,
  • Exequiel Dellota Jr.,
  • Benjamin Merz,
  • Bhavna Chawla,
  • Swagata Kar,
  • Antonio Lanzavecchia,
  • Federica Sallusto,
  • Nicholas M. Riley,
  • Stuart Turville,
  • Lisa Purcell,
  • Michael S. Diamond,
  • David Veesler

摘要

The protease TMPRSS2 facilitates coronavirus infections, yet its mechanism of viral glycoprotein recognition remains unclear. Here we show that, following ACE2 engagement of the SARS-CoV-2 spike (S) inducing the early fusion intermediate conformation (E-FIC), TMPRSS2 cleaves the R815 S2′ site and promotes fusogenic conformational changes leading to viral entry. We unveil TMPRSS2 recognition of S2′, identify key residues modulating binding specificity and demonstrate that S2′ site-directed broadly neutralizing antibodies target E-FIC and inhibit viral entry by blocking TMPRSS2 access. We computationally designed stabilized E-FIC as a vaccine candidate, overcoming the transient nature of this state. We describe a TMPRSS2-directed monoclonal antibody inhibiting several coronaviruses, including SARS-CoV-2 variants and protecting mice against SARS-CoV-2 challenge. These results outline the mechanistic role of TMPRSS2 and S2′ site-directed antibodies in coronavirus entry.