SARS-CoV-2 Spike protein-Angiotensin-converting enzyme 2 interface and Transmembrane serine protease 2 (Spike-ACE2/TMPRSS2)

The SARS-CoV-2 Spike protein-ACE2 interface and Transmembrane serine protease 2 (TMPRSS2) represent the essential molecular gateway for viral entry into human host cells (Hoffmann et al., 2020, Cell). The process is initiated when the receptor-binding domain of the viral Spike protein attaches to the host cell surface receptor, Angiotensin-converting enzyme 2 (ACE2), which is widely expressed in the lungs, heart, and kidneys (UniProt P59891). Subsequently, the host protease TMPRSS2 (UniProt O15393) cleaves the Spike protein at specific sites, a process known as priming, which triggers the conformational changes necessary for membrane fusion and viral genome entry. This pathway is the primary target for many COVID-19 therapeutics, including monoclonal antibodies like Sotrovimab that block the Spike-ACE2 interaction and protease inhibitors like Camostat mesylate that target TMPRSS2 (NIH COVID-19 Treatment Guidelines). Because these components are vital for infection, they are central to understanding viral pathogenesis and developing effective countermeasures against SARS-CoV-2 and its variants.

Other names

SARS-CoV-2 entry pathwaySpike-ACE2 complexTMPRSS2 proteaseHost-viral entry machinerySpike-ACE2-TMPRSS2 axis

Inhibition of viral attachment via Spike-ACE2 blockade and inhibition of viral priming via TMPRSS2 protease inhibition (Hoffmann et al., 2020).