3C-like protease

Source: Wikipedia, the free encyclopedia.
See also: COVID-19 drug development
ExPASy
NiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Search
PMCarticles
PubMedarticles
NCBIproteins
Peptidase C30, Coronavirus endopeptidase
Identifiers
SymbolPeptidase_C30
SCOP2
d1q2wb1 / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

The 3C-like protease (3CLpro) or main protease (Mpro), formally known as C30 endopeptidase or 3-chymotrypsin-like protease,

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

nonstructural protein 5 (nsp5). The "3C" in the common name refers to the 3C protease (3Cpro) which is a homologous protease found in picornaviruses
.

Function

The 3C-like protease is able to

SARS coronavirus 3CLpro can for instance self-cleave the following peptides:[3][4][5]

TSAVLQ-SGFRK-NH2 and SGVTFQ-GKFKK are the two peptides corresponding to the two self-cleavage sites of the SARS 3C-like proteinase

The protease is important in the processing of the coronavirus

replicase polyprotein (P0C6U8). It is the main protease in coronaviruses and corresponds to nonstructural protein 5 (nsp5).[6] It cleaves the coronavirus polyprotein at 11 conserved sites. The 3CL protease has a cysteine-histidine catalytic dyad at its active site.[4] The sulfur of the cysteine acts as a nucleophile and the imidazole ring of the histidine as a general base.[7]

Substrate preferences for 3CL proteases (from table 2)[8]
Position Substrate preference
P5 No strong preference
P4 Small
hydrophobic
residues
P3 Positively charged residue
P2 High hydrophobicity and absence of beta-branch
P1 Glutamine
P1' Small residues
P2' Small residues
P3' No strong preference

Nomenclature

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

Nirmatrelvir bound to 3CL PDB: 7RFW​
Nirmatrelvir, a 3CLpro inhibitor developed by Pfizer in phase II/III clinical trials as a combination drug with ritonavir.[9][10]

The protease 3CLpro is used as a

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[13] for a treatment of SARS-CoV-2 infection.[14][15][16][17][18]

A number of

PF-07304814 (lufotrelvir) entered clinical trials in September 2020.[23]

After clinical trials, in December 2021, the oral medication

emergency use authorizations (EUA), as part of the nirmatrelvir/ritonavir combination therapy (brand name Paxlovid).[24][25] In May 2023, the medication got full FDA approval for high-risk adults, while children 12–18 were still covered under the EUA.[26]

The 3C-like protease inhibitor ensitrelvir received authorization to treat COVID-19 in Japan in 2022.[27][28]

In 2022, an ultralarge virtual screening campaign of 235 million molecules was able to identify a novel broad-spectrum inhibitor targeting the main protease of several coronaviruses. It is unusually not a peptidomimetic.[29]

water molecules.[1]

Other 3C(-like) proteases

3C-like proteases (3C(L)pro) are widely found in

substrate specificity and inhibitor effectiveness. They are divided into subfamilies by sequence similarity, corresponding to the family of viruses they are found in:[30]

Additional members are known from Potyviridae and non-Coronaviridae Nidovirales.[31]

See also

References

  1. ^
    PMID 32321856
    .
  2. PMID 34502033
    .
  3. PMID 17605471
    .
  4. ^
    PMID 14561748
    .
  5. PMID 18845442
    .
  6. PMID 25720466
    . See section: Virion Structure.
  7. PMID 20167482
    .
  8. PMID 22073294
    .
  9. PMID 34029993
    .
  10. ^ "Pfizer begins dosing in Phase II/III trial of antiviral drug for Covid-19". Clinical Trials Arena. 2 September 2021.
  11. PMID 25039866
    .
  12. S2CID 220304661
    .
  13. PMID 1738140
    .
  14. PMID 12746549
    .
  15. PMID 31312413
    .
  16. PMID 26149721
    .
  17. PMID 32045235
    .
  18. PMID 32198291
    .
  19. PMID 33556871
    .
  20. PMID 32022370
    .
  21. PMID 32226821
    .
  22. PMID 21936817
    .
  23. ^ "First-In-Human Study To Evaluate Safety, Tolerability, And Pharmacokinetics Following Single Ascending And Multiple Ascending Doses of PF-07304814 In Hospitalized Participants With COVID-19". Clinical Trials. 24 June 2021. Retrieved 3 July 2021.
  24. ^ Fact sheet for healthcare providers: Emergency Use Authorization for Paxlovid (PDF) (Technical report). Pfizer. 22 December 2021. LAB-1492-0.8. Archived from the original on 23 December 2021.
  25. ^ "Pfizer Receives U.S. FDA Emergency Use Authorization for Novel COVID-19 Oral Antiviral Treatment" (Press release). Pfizer. 22 December 2021. Archived from the original on 22 December 2021. Retrieved 22 December 2021 – via Business Wire.
  26. ^ "FDA Approves First Oral Antiviral for Treatment of COVID-19 in Adults". U.S. Food and Drug Administration (FDA) (Press release). 26 May 2023. Retrieved 26 May 2023. Public Domain This article incorporates text from this source, which is in the public domain.
  27. ^ "Xocova (Ensitrelvir Fumaric Acid) Tablets 125mg Approved in Japan for the Treatment of SARS-CoV-2 Infection, under the Emergency Regulatory Approval System". Shionogi (Press release). 22 November 2022. Retrieved 28 November 2022.
  28. ^ Lenharo, Mariana (18 October 2023). "New Pill Helps COVID Smell and Taste Loss Fade Quickly". Scientific American. Retrieved 28 October 2023.
  29. PMID 35142215
    .
  30. PMID 22915796
    .
  31. PMID 12502857
    .

Further reading

External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=3C-like_protease&oldid=1192071659"