tetano
Editor, Senior Moderator
Nat Struct Mol Biol
. 2026 Apr 28.
doi: 10.1038/s41594-026-01801-y. Online ahead of print.
TMPRSS2-mediated coronavirus spike activation and inhibition
Matthew McCallum[SUP] #[/SUP][SUP] 1 2 [/SUP], James Brett Case[SUP] #[/SUP][SUP] 3 4 [/SUP], Jack T Brown[SUP] #[/SUP][SUP] 1 [/SUP], Young-Jun Park[SUP] #[/SUP][SUP] 1 5 [/SUP], Jimin Lee[SUP] 1 [/SUP], Emmajay Sutherland[SUP] 6 [/SUP], Anupriya Aggarwal[SUP] 7 [/SUP], Cecily Gibson[SUP] 1 5 [/SUP], Florian A Lempp[SUP] 8 [/SUP], Cameron Stewart[SUP] 1 [/SUP], M Alejandra Tortorici[SUP] 1 [/SUP], Shilpa Sanapala[SUP] 3 [/SUP], Jun Siong Low[SUP] 9 10 11 [/SUP], Daniel Asarnow[SUP] 1 [/SUP], Dana Bohan[SUP] 8 [/SUP], Exequiel Dellota Jr[SUP] 8 [/SUP], Benjamin Merz[SUP] 1 [/SUP], Bhavna Chawla[SUP] 12 [/SUP], Swagata Kar[SUP] 12 [/SUP], Antonio Lanzavecchia[SUP] 13 14 [/SUP], Federica Sallusto[SUP] 9 10 [/SUP], Nicholas M Riley[SUP] 6 [/SUP], Stuart Turville[SUP] 7 [/SUP], Lisa Purcell[SUP] 8 15 [/SUP], Michael S Diamond[SUP] 16 17 18 [/SUP], David Veesler[SUP] 19 20 [/SUP]
Affiliations
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.
. 2026 Apr 28.
doi: 10.1038/s41594-026-01801-y. Online ahead of print.
TMPRSS2-mediated coronavirus spike activation and inhibition
Matthew McCallum[SUP] #[/SUP][SUP] 1 2 [/SUP], James Brett Case[SUP] #[/SUP][SUP] 3 4 [/SUP], Jack T Brown[SUP] #[/SUP][SUP] 1 [/SUP], Young-Jun Park[SUP] #[/SUP][SUP] 1 5 [/SUP], Jimin Lee[SUP] 1 [/SUP], Emmajay Sutherland[SUP] 6 [/SUP], Anupriya Aggarwal[SUP] 7 [/SUP], Cecily Gibson[SUP] 1 5 [/SUP], Florian A Lempp[SUP] 8 [/SUP], Cameron Stewart[SUP] 1 [/SUP], M Alejandra Tortorici[SUP] 1 [/SUP], Shilpa Sanapala[SUP] 3 [/SUP], Jun Siong Low[SUP] 9 10 11 [/SUP], Daniel Asarnow[SUP] 1 [/SUP], Dana Bohan[SUP] 8 [/SUP], Exequiel Dellota Jr[SUP] 8 [/SUP], Benjamin Merz[SUP] 1 [/SUP], Bhavna Chawla[SUP] 12 [/SUP], Swagata Kar[SUP] 12 [/SUP], Antonio Lanzavecchia[SUP] 13 14 [/SUP], Federica Sallusto[SUP] 9 10 [/SUP], Nicholas M Riley[SUP] 6 [/SUP], Stuart Turville[SUP] 7 [/SUP], Lisa Purcell[SUP] 8 15 [/SUP], Michael S Diamond[SUP] 16 17 18 [/SUP], David Veesler[SUP] 19 20 [/SUP]
Affiliations
- PMID: 42050172
- DOI: 10.1038/s41594-026-01801-y
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.