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Structure and activity of human TMPRSS2 protease implicated in SARS-CoV-2 activation

2022; Nature Portfolio; Volume: 18; Issue: 9 Linguagem: Inglês

10.1038/s41589-022-01059-7

1552-4469

Bryan J. Fraser, Serap Beldar, Almagul Seitova, Ashley Hutchinson, Dhiraj Mannar, Yanjun Li, Daniel Kwon, Ruiyan Tan, Ryan P. Wilson, Karoline Leopold, Sriram Subramaniam, Levon Halabelian, C.H. Arrowsmith, François Bénard,

vaccines and immunoinformatics approaches

Transmembrane protease, serine 2 (TMPRSS2) has been identified as key host cell factor for viral entry and pathogenesis of SARS-CoV-2. Specifically, TMPRSS2 proteolytically processes the SARS-CoV-2 Spike (S) protein, enabling virus–host membrane fusion and infection of the airways. We present here a recombinant production strategy for enzymatically active TMPRSS2 and characterization of its matured proteolytic activity, as well as its 1.95 Å X-ray cocrystal structure with the synthetic protease inhibitor nafamostat. Our study provides a structural basis for the potent but nonspecific inhibition by nafamostat and identifies distinguishing features of the TMPRSS2 substrate binding pocket that explain specificity. TMPRSS2 cleaved SARS-CoV-2 S protein at multiple sites, including the canonical S1/S2 cleavage site. We ranked the potency of clinical protease inhibitors with half-maximal inhibitory concentrations ranging from 1.4 nM to 120 µM and determined inhibitor mechanisms of action, providing the groundwork for drug development efforts to selectively inhibit TMPRSS2. The first crystal structure of human TMPRSS2, a proteolytic driver of SARS-CoV-2 infection in airways and an antiviral target, reveals structural features of viral spike protein and protease inhibitor binding.