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TMPRSS2-mediated coronavirus spike activation and inhibition

ABSTRACT: The human protease TMPRSS2 facilitates entry of many respiratory viruses into cells, including coronaviruses and influenza viruses, yet its mechanism or viral glycoprotein recognition remains unclear. Here, we show that following ACE2 engagement and formation of an early fusion intermediate SARS-CoV-2 spike (S) conformation (E-FIC), TMPRSS2 cleaves the R815 S2' site and triggers large-scale conformational changes required for membrane fusion and viral entry. Using cryo-electron microscopy, we resolve the interactions between TMPRSS2 and S2' and identify key residues modulating binding specificity. We further reveal that S2' site-directed broadly neutralizing antibodies recognise E-FIC and inhibit viral entry by interfering with TMPRSS2 access. We describe a TMPRSS2-directed monoclonal antibody that inhibits entry of several coronaviruses into TMPRSS2 expressing cells and protects against SARS-CoV-2 challenge in vivo. These results elucidate the mechanistic role of TMPRSS2 andS2' site-directed broadly neutralizing antibodies in coronavirus entry, and establish host-directed counter-measures as a paradigm for viral pandemic preparedness.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Emmajay Sutherland

LAB HEAD: Nicholas M. Riley

PROVIDER: PXD069687 | Pride | 2026-03-27

REPOSITORIES: Pride

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			Action	DRS
	2025-10-11-decoys-contam-All_proteins.fasta.fas	Fasta
	251009_ES_E00049_c00014_SA_1a_2uL.raw	Raw
	251009_ES_E00049_c00014_SA_1b_2uL.raw	Raw
	251009_ES_E00049_c00014_SA_1c_2uL.raw	Raw
	251009_ES_E00049_c00014_SA_2a_2uL.raw	Raw

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