Angiotensin-converting enzyme 2 and SARS-CoV-2 main protease (ACE2 / Mpro)

Angiotensin-converting enzyme 2 (ACE2) and the SARS-CoV-2 main protease (Mpro, or 3CLpro) are two distinct proteins that play central, yet different, roles in the COVID-19 infectious cycle. ACE2 is a human membrane-bound carboxypeptidase that functions as the primary receptor for the SARS-CoV-2 spike protein, facilitating viral attachment and entry into host cells (UniProt Q9BYF1). Beyond its role in infection, ACE2 is a key regulator of the renin-angiotensin system, converting the vasoconstrictor angiotensin II into the vasodilator angiotensin (1-7) (PubMed: 32275855). The SARS-CoV-2 main protease (Mpro) is a viral cysteine protease (NSP5) essential for processing the large polyproteins translated from the viral RNA into individual functional non-structural proteins required for viral replication (UniProt P0DTD1). While ACE2 is a host target often addressed by blocking its interaction with the virus using monoclonal antibodies, Mpro is a direct viral target for small-molecule inhibitors like nirmatrelvir (FDA: Paxlovid) (PubMed: 34785091). Together, these proteins represent the two most critical nodes for therapeutic intervention against SARS-CoV-2, though they belong to entirely different biological classes.

Other names

ACEHMetalloprotease 23C-like proteinase3CLproNSP5C30 endopeptidaseSARS-CoV-2 MproAngiotensin-converting enzyme homolog

Inhibition of the viral 3C-like protease (Mpro) to prevent the processing of polyproteins pp1a and pp1ab into functional non-structural proteins, thereby halting viral replication (PubMed: 34785091). Additionally, blocking the interaction between the host Angiotensin-converting enzyme 2 (ACE2) receptor and the viral spike protein to prevent viral entry into host cells (PubMed: 32275855).