Severe acute respiratory syndrome coronavirus 2 3C-like protease and viral entry proteins (3CLpro/Entry)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3C-like protease (3CLpro), also known as the main protease (Mpro), is a highly conserved cysteine protease (nsp5) essential for processing viral polyproteins into functional non-structural proteins required for the replication-transcription complex [UniProt P0DTD1]. It is the primary target for small-molecule antivirals such as nirmatrelvir and ensitrelvir, which inhibit the enzyme's catalytic activity to halt viral replication [Science, 2020]. Viral entry refers to the multi-step process by which the virus infects host cells, initiated by the binding of the viral Spike (S) protein to the host Angiotensin-converting enzyme 2 (ACE2) receptor [Cell, 2020]. This entry is often facilitated by host cell surface proteases like Transmembrane serine protease 2 (TMPRSS2), which cleaves the Spike protein to enable membrane fusion [Nature, 2020]. Therapeutic interventions for entry include neutralizing monoclonal antibodies that target the Spike protein and host protease inhibitors like camostat [NIH, 2023]. This target entry is considered incorrect as a single molecular entity because it conflates a specific viral enzyme with a complex multi-protein pathway involving both viral and host components.

Other names

SARS-CoV-2 3CLproMain proteaseMpronsp5SARS-CoV-2 Spike proteinAngiotensin-converting enzyme 2ACE2TMPRSS2Viral entry pathway

Inhibition of the 3C-like protease prevents the proteolytic cleavage of the pp1a and pp1ab polyproteins into individual non-structural proteins, thereby blocking the formation of the viral replication-transcription complex. Viral entry inhibition involves blocking the interaction between the viral Spike protein and the host ACE2 receptor or inhibiting host proteases like TMPRSS2 that are required for viral-host membrane fusion.