Targeting the viral-entry facilitators of SARS-CoV-2 as a therapeutic strategy in COVID-19.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19) infection, which has emerged as a global pandemic causing serious concerns. Lack of specific and effective therapeutics for the treatment of COVID-19 is a major concern and the development of vaccines is another important aspect in managing the infection effectively. The first step in the SARS-CoV-2 pathogenesis is the viral entry and it is mediated by its densely glycosylated spike protein (S-protein). Similar to the SARS-CoV, SARS-CoV-2 also engages angiotensin-converting enzyme 2 (ACE2) as the host cell entry receptor. In addition to ACE2, several recent studies have implicated the crucial role of cell surface heparan sulfate (HS) as a necessary assisting cofactor for ACE2-mediated SARS-CoV-2 entry. Furthermore, SARS-CoV-2 was also identified to use both endosomal cysteine proteases cathepsin B and L (CatB/L) and the transmembrane serine protease 2 (TMPRSS2) for the pivotal role of S-protein priming mediating viral entry. As the entry of SARS-CoV-2 into host cells is mandatory for viral infection, it becomes an extremely attractive therapeutic intervention point. In this regard, this review will focus on the therapeutic targeting of the crucial steps of SARS-CoV-2 viral entry like S-protein/ACE2 interaction and S-protein priming by host cell proteases. In addition, this review will also give insights to the readers on several therapeutic opportunities, pharmacological targeting of the viral-entry facilitators like S-Protein, ACE2, cell surface HS, TMPRSS2, and CatB/L and evidence for those drugs currently ongoing clinical studies.

Muralidar S ，Gopal G ，Visaga Ambi S 《-》

Contributions of human ACE2 and TMPRSS2 in determining host-pathogen interaction of COVID-19.

Senapati S ，Banerjee P ，Bhagavatula S ，Kushwaha PP ，Kumar S ... -  《-》

Distinctive Roles of Furin and TMPRSS2 in SARS-CoV-2 Infectivity.

Essalmani R ，Jain J ，Susan-Resiga D ，Andréo U ，Evagelidis A ，Derbali RM ，Huynh DN ，Dallaire F ，Laporte M ，Delpal A ，Sutto-Ortiz P ，Coutard B ，Mapa C ，Wilcoxen K ，Decroly E ，Nq Pham T ，Cohen ÉA ，Seidah NG ... -  《-》

The TMPRSS2 Inhibitor Nafamostat Reduces SARS-CoV-2 Pulmonary Infection in Mouse Models of COVID-19.

Li K ，Meyerholz DK ，Bartlett JA ，McCray PB Jr ... -  《mBio》

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor.

The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.

Hoffmann M ，Kleine-Weber H ，Schroeder S ，Krüger N ，Herrler T ，Erichsen S ，Schiergens TS ，Herrler G ，Wu NH ，Nitsche A ，Müller MA ，Drosten C ，Pöhlmann S ... -  《-》