From Wikipedia the free encyclopedia
|SARS coronavirus main proteinase|
|PDB structures||RCSB PDB PDBe PDBsum|
|Peptidase C30, Coronavirus endopeptidase|
|SCOP2||d1q2wb1 / SCOPe / SUPFAM|
The 3C-like protease (3CLpro) or Mpro, formally known as C30 Endopeptidase, is the main protease found in coronaviruses. It cleaves the coronavirus polyprotein at eleven conserved sites. It is a cysteine protease and a member of the PA clan of proteases. It has a cysteine-histidine catalytic dyad at its active site and cleaves a Gln–(Ser/Ala/Gly) peptide bond.
The Enzyme Commission refers to this family as SARS coronavirus main proteinase (Mpro; EC 220.127.116.11). The 3CL protease corresponds to coronavirus nonstructural protein 5 (nsp5). The "3C" in the common name refers to the 3C protease (3Cpro) which is a homologous protease found in picornaviruses.
The 3C-like protease is able to catalytically cleave a peptide bond between a glutamine at position P1 and a small amino acid (serine, alanine, or glycine) at position P1'. The SARS coronavirus 3CLpro can for instance self-cleave the following peptides:
The protease is important in the processing of the coronavirus replicase polyprotein ( It cleaves the coronavirus polyprotein at 11 conserved sites. The 3CL protease has a cysteine-histidine catalytic dyad at its active site. The sulfur of the cysteine acts as a nucleophile and the imidazole ring of the histidine as a general base.). It is the main protease in coronaviruses and corresponds to nonstructural protein 5 (nsp5).
Alternative names provided by the EC include 3CLpro, 3C-like protease, coronavirus 3C-like protease, Mpro, SARS 3C-like protease, SARS coronavirus 3CL protease, SARS coronavirus main peptidase, SARS coronavirus main protease, SARS-CoV 3CLpro enzyme, SARS-CoV main protease, SARS-CoV Mpro and severe acute respiratory syndrome coronavirus main protease.
As a treatment target
The protease 3CLpro is a potential drug target for coronavirus infections due to its essential role in processing the polyproteins that are translated from the viral RNA. The X-ray structures of the unliganded SARS-CoV-2 protease 3CLpro and its complex with an α-ketoamide inhibitor provides a basis for design of α-ketoamide inhibitors for a treatment of SARS-CoV-2 infection. Potential protease inhibitors being developed against 3CLpro and homologous 3Cpro include CLpro-1, GC376, rupintrivir, PF-07304814, PF-07321332, chemical 11a, and chemical 11b. The long-term molecular dynamics simulations (1.50 µs) study reported, oolonghomobisflavan-A (a tea bioactive) as a more potent inhibitor of the Mpro of SARS-CoV-2 than previously suggested repurposed anti-HIV drugs.  A robust computational strategy stated that the in-house synthesized acridinedione analogs DSPD-2 and DSPD-6 showed more favorable MM-PBSA interaction energies and were seated more deeply inside the binding pocket of Mpro than the antiviral drug (saquinavir). These acridinedione analogs have acceptable ADMET values and low toxicity profile. The binding potential of molecules to the binding site of SARS-CoV-2 Mpro could be increased by targeting the molecules to interact more efficiently with residues of the S1 subsite of the binding pocket.
Other 3C(-like) proteases
3C-like proteases (3C(L)pro) are widely found in (+)ssRNA viruses. All of them are cysteine proteases with a chymotrypsin-like fold (PA clan), using a catalytic dyad or triad. They share some general similarities on substrate specificity and inhibitor effectiveness. They are divided into subfamilies by sequence similarity, corresponding to the family of viruses they are found in:
- This entry is the coronavirus 3CLpro.
- Picornaviridae have a picronavirus 3Cpro (EC 18.104.22.168; InterPro: IPR000199; MEROPS C03). This is the earliest-studied family. Examples include the ones found in poliovirus and in rhinovirus (both are members of genus Enterovirus).
- Caliciviridae have a 3CLpro (InterPro: IPR001665; MEROPS C37). Examples include the one found in Norwalk virus.
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See section: Virion Structure.
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