Distinctive Roles of Furin and TMPRSS2 in SARS-CoV-2 Infectivity
Rachid Essalmani, Jaspreet Jain, Delia Susan‐Resiga, Ursula Andréo, Alexandra Evagelidis, Rabeb Mouna Derbali, David Huynh, Frédéric Dallaire, Mélanie Laporte, Adrien Delpal, Priscila Sutto‐Ortiz, Bruno Coutard, Claudine Mapa, Keith Wilcoxen, Étienne Decroly, Tram N. Q. Pham, Éric A. Cohen, Nabil G. Seidah
Abstract
SARS-CoV-2, the etiological agent of COVID-19, has so far resulted in >6.1 million deaths worldwide. The spike protein (S) of the virus directs infection of the lungs and other tissues by binding the angiotensin-converting enzyme 2 (ACE2) receptor. For effective infection, the S protein is cleaved at two sites: S1/S2 and S2'. Cleavage at S1/S2 induces a conformational change favoring the S protein recognition by ACE2. The S2' cleavage is critical for triggering membrane fusion and virus entry into host cells. Our study highlights the complex dynamics of interaction between the S protein, ACE2, and the host proteases furin and TMPRSS2 during SARS-CoV-2 entry and suggests that the combination of a nontoxic furin inhibitor with a TMPRSS2 inhibitor significantly reduces viral entry in lung cells, as evidenced by an average synergistic ∼95% reduction of viral infection. This represents a powerful novel antiviral approach to reduce viral spread in individuals infected by SARS-CoV-2 or future related coronaviruses.