Biology:3C-like protease

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Short description: Class of enzymes
DOI.10.1126.science.abb4489.S2.png
SARS-CoV-2 main proteinase dimer with the catalytic dyad (H41; C145) in complex with a covalent peptidomimetic protease inhibitor ("11a", magenta). From PDB: 6LZE​.[1]
Identifiers
EC number3.4.22.69
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Peptidase C30, Coronavirus endopeptidase
Identifiers
SymbolPeptidase_C30
PfamPF05409
InterProIPR008740
PROSITEPS51442
MEROPSC30
SCOP2d1q2wb1 / SCOPe / SUPFAM

The 3C-like protease (3CLpro) or main protease (Mpro), formally known as C30 endopeptidase or 3-chymotrypsin-like protease,[2] 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 3.4.22.69). 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.

Function

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:[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 drug target for coronavirus infections due to its essential role in processing the polyproteins that are translated from the viral RNA.[11][12] 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[13] for a treatment of SARS-CoV-2 infection.[14][15][16][17][18]

A number of protease inhibitors are being developed targeting 3CLpro and homologous 3Cpro, including CLpro-1, GC376, rupintrivir, lufotrelvir, PF-07321332, and AG7404.[19][20][21][22][1] The intravenous administered prodrug PF-07304814 (lufotrelvir) entered clinical trials in September 2020.[23]

After clinical trials, in December 2021, the oral medication nirmatrelvir (formerly PF-07321332) became commercially available under 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]

A ligand-binding diagram showing the amino acid residues in contact with a covalently bound peptidomimetic protease inhibitor. The small red spheres are water molecules.[1]

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:[30]

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

See also

References

  1. ↑ 1.0 1.1 1.2 "Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease". Science 368 (6497): 1331–1335. June 2020. doi:10.1126/science.abb4489. PMID 32321856. Bibcode: 2020Sci...368.1331D. 
  2. ↑ "Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations". International Journal of Molecular Sciences 22 (17): 9124. August 2021. doi:10.3390/ijms22179124. PMID 34502033. 
  3. ↑ "Substrate specificity profiling and identification of a new class of inhibitor for the major protease of the SARS coronavirus". Biochemistry 46 (30): 8744–52. July 2007. doi:10.1021/bi0621415. PMID 17605471. 
  4. ↑ 4.0 4.1 "Biosynthesis, purification, and substrate specificity of severe acute respiratory syndrome coronavirus 3C-like proteinase". The Journal of Biological Chemistry 279 (3): 1637–42. January 2004. doi:10.1074/jbc.m310875200. PMID 14561748. 
  5. ↑ "Evaluation of peptide-aldehyde inhibitors using R188I mutant of SARS 3CL protease as a proteolysis-resistant mutant". Bioorganic & Medicinal Chemistry 16 (21): 9400–8. November 2008. doi:10.1016/j.bmc.2008.09.057. PMID 18845442. 
  6. ↑ "Coronaviruses: an overview of their replication and pathogenesis". Coronaviruses. Methods in Molecular Biology. 1282. Springer. 2015. pp. 1–23. doi:10.1007/978-1-4939-2438-7_1. ISBN 978-1-4939-2438-7. "See section: Virion Structure." 
  7. ↑ "SARS-CoV 3CLpro inhibitory effects of quinone-methide triterpenes from Tripterygium regelii". Bioorganic & Medicinal Chemistry Letters 20 (6): 1873–6. March 2010. doi:10.1016/j.bmcl.2010.01.152. ISSN 0960-894X. PMID 20167482. 
  8. ↑ "Profiling of substrate specificities of 3C-like proteases from group 1, 2a, 2b, and 3 coronaviruses". PLOS ONE 6 (11): e27228. 2011. doi:10.1371/journal.pone.0027228. PMID 22073294. Bibcode: 2011PLoSO...627228C. 
  9. ↑ "Considerations for the discovery and development of 3-chymotrypsin-like cysteine protease inhibitors targeting SARS-CoV-2 infection". Curr Opin Virol 49: 36–40. August 2021. doi:10.1016/j.coviro.2021.04.006. PMID 34029993. 
  10. ↑ "Pfizer begins dosing in Phase II/III trial of antiviral drug for Covid-19.". Clinical Trials Arena. 2 September 2021. https://www.clinicaltrialsarena.com/news/pfizer-antiviral-covid-trial/. 
  11. ↑ "From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design". FEBS Journal 281 (18): 4085–4096. July 2014. doi:10.1111/febs.12936. PMID 25039866. 
  12. ↑ "The SARS-CoV-2 main protease as a drug target". Bioorganic & Medicinal Chemistry Letters 30 (17): 127377. July 2020. doi:10.1016/j.bmcl.2020.127377. PMID 32738988. 
  13. ↑ "alpha-Keto amide inhibitors of aminopeptidases". Journal of Medicinal Chemistry 35 (3): 451–6. February 1992. doi:10.1021/jm00081a005. PMID 1738140. 
  14. ↑ "Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs". Science 300 (5626): 1763–7. June 2003. doi:10.1126/science.1085658. PMID 12746549. Bibcode: 2003Sci...300.1763A. 
  15. ↑ "Synthesis and Biological Activity of Peptide α-Ketoamide Derivatives as Proteasome Inhibitors". ACS Medicinal Chemistry Letters 10 (7): 1086–1092. July 2019. doi:10.1021/acsmedchemlett.9b00233. PMID 31312413. 
  16. ↑ "A G-quadruplex-binding macrodomain within the "SARS-unique domain" is essential for the activity of the SARS-coronavirus replication-transcription complex". Virology 484: 313–22. October 2015. doi:10.1016/j.virol.2015.06.016. PMID 26149721. 
  17. ↑ "α-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment". Journal of Medicinal Chemistry 63 (9): 4562–4578. February 2020. doi:10.1021/acs.jmedchem.9b01828. PMID 32045235. 
  18. ↑ "Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors". Science 368 (6489): 409–412. March 2020. doi:10.1126/science.abb3405. PMID 32198291. Bibcode: 2020Sci...368..409Z. 
  19. ↑ "An update review of emerging small-molecule therapeutic options for COVID-19". Biomedicine & Pharmacotherapy 137: 111313. May 2021. doi:10.1016/j.biopha.2021.111313. PMID 33556871. 
  20. ↑ "Learning from the Past: Possible Urgent Prevention and Treatment Options for Severe Acute Respiratory Infections Caused by 2019-nCoV". ChemBioChem 21 (5): 730–738. March 2020. doi:10.1002/cbic.202000047. PMID 32022370. 
  21. ↑ "Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases". ACS Central Science 6 (3): 315–331. March 2020. doi:10.1021/acscentsci.0c00272. PMID 32226821. 
  22. ↑ "Recent development of 3C and 3CL protease inhibitors for anti-coronavirus and anti-picornavirus drug discovery". Biochemical Society Transactions 39 (5): 1371–5. October 2011. doi:10.1042/BST0391371. 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.. 24 June 2021. https://clinicaltrials.gov/ct2/show/NCT04535167. Retrieved 3 July 2021. 
  24. ↑ Template:Cite tech report
  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. 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". https://www.scientificamerican.com/article/new-pill-helps-covid-smell-and-taste-loss-fade-quickly/. 
  29. ↑ "Ultralarge Virtual Screening Identifies SARS-CoV-2 Main Protease Inhibitors with Broad-Spectrum Activity against Coronaviruses". J Am Chem Soc 144 (7): 2905–2920. February 2022. doi:10.1021/jacs.1c08402. ISSN 0002-7863. PMID 35142215. 
  30. ↑ "Broad-spectrum antivirals against 3C or 3C-like proteases of picornaviruses, noroviruses, and coronaviruses". Journal of Virology 86 (21): 11754–62. November 2012. doi:10.1128/JVI.01348-12. PMID 22915796. 
  31. ↑ "The 3C-like proteinase of an invertebrate nidovirus links coronavirus and potyvirus homologs". Journal of Virology 77 (2): 1415–26. January 2003. doi:10.1128/jvi.77.2.1415-1426.2003. PMID 12502857. 

Further reading

External links



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