RT Journal Article
SR Electronic
T1 Furin cleaves SARS-CoV-2 spike-glycoprotein at S1/S2 and S2’ for viral fusion/entry: indirect role of TMPRSS2
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.12.18.423106
DO 10.1101/2020.12.18.423106
A1 Rachid Essalmani
A1 Jaspreet Jain
A1 Delia Susan-Resiga
A1 Ursula Andréo
A1 Alexandra Evagelidis
A1 Rabeb Mouna Derbali
A1 David N. Huynh
A1 Frédéric Dallaire
A1 Mélanie Laporte
A1 Adrien Delpal
A1 Priscila Sutto-Ortiz
A1 Bruno Coutard
A1 Claudine Mapa
A1 Keith Wilcoxen
A1 Étienne Decroly
A1 Tram NQ Pham
A1 Éric A. Cohen
A1 Nabil G. Seidah
YR 2020
UL http://biorxiv.org/content/early/2020/12/20/2020.12.18.423106.abstract
AB The Spike (S)-protein of SARS-CoV-2 binds host-cell receptor ACE2 and requires proteolytic “priming” (S1/S2) and “fusion-activation” (S2’) for viral entry. The S-protein furin-like motifs PRRAR685↓ and KPSKR815↓ indicated that proprotein convertases promote virus entry. We demonstrate that furin and PC5A induce cleavage at both sites, ACE2 enhances S2’ processing, and their pharmacological inhibition (BOS-inhibitors) block endogenous cleavages. S1/S2-mutations (μS1/S2) limit S-protein-mediated cell-to-cell fusion, similarly to BOS-inhibitors. Unexpectedly, TMPRSS2 does not cleave at S1/S2 or S2’, but it can: (i) cleave/inactivate S-protein into S2a/S2b; (ii) shed ACE2; (iii) cleave S1-subunit into secreted S1’, activities inhibited by Camostat. In lung-derived Calu-3 cells, BOS-inhibitors and µS1/S2 severely curtail “pH-independent” viral entry, and BOS-inhibitors alone/with Camostat potently reduce infectious viral titer and cytopathic effects. Overall, our results show that: furin plays a critical role in generating fusion-competent S-protein, and indirectly, TMPRSS2 promotes viral entry, supporting furin and TMPRSS2 inhibitors as potential antivirals against SARS-CoV-2.Competing Interest StatementThe authors have declared no competing interest.