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CoV 3C-like (main) protease

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Target not currently curated in GtoImmuPdb

Target id: 3111

Nomenclature: CoV 3C-like (main) protease

Family: Coronavirus (CoV) proteins

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
SARS-CoV-2 - 306
SARS-CoV - 306
Gene and Protein Information Comments
The SARS-CoV main protease (Mpro) is a 306 amino acid cysteine protease that is encoded in the viral RNA replicase gene. It is amino acids 3241-3546 of the full length SARS-CoV polyprotein (3919 amino acids).
The SARS-CoV-2 Mpro is also 306 amino acids. The provisional RefSeq YP_009725301 has been allocated to SARS-CoV-2 M6LU7 [9]. The amino acid sequence for Mpro from the PDB entry has been submitted to the NCBI as 6LU7_A (Chain A, SARS-CoV-2 main protease). A UniProt ID will be released with UniProt release 2020_02 (due April 22nd, 2020). Pre-release information provides the ID P0DTD1 for the complete SARS-CoV-2 replicase polyprotein (length 7096 amino acids). SARS-CoV-2 Mpro is amino acids 3264-3569 of the full length polyprotein.
Previous and Unofficial Names Click here for help
3c-like proteinase | SARS-CoV-2 Mpro | Chain A, 3c-like Proteinase | 3CL protease | Mpro | nsp5
Database Links Click here for help
ChEMBL Target CHEMBL3927 (SARS-CoV)
RefSeq Protein
UniProtKB P0C6U8 (SARS-CoV)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure (monoclinic form) of the complex resulting from the reaction between SARS-CoV-2 (2019-nCoV) main protease and tert-butyl (1-((S)-1-(((S)-4-(benzylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate (alpha-ketoamide 13b)
PDB Id:  6Y2F
Ligand:  compound 13b [PMID: 32198291]
Resolution:  1.95Å
Species:  SARS-CoV-2
References:  23
Image of receptor 3D structure from RCSB PDB
Description:  The crystal structure of COVID-19 main protease in complex with an inhibitor N3 (PRD_002214).
PDB Id:  6LU7
Ligand:  PRD_002214
Resolution:  2.16Å
Species:  SARS-CoV-2
References:  9
Image of receptor 3D structure from RCSB PDB
Description:  The crystal structure of COVID-19 main protease in complex with an inhibitor 11a
PDB Id:  6LZE
Ligand:  compound 11a [PMID: 32321856]
Resolution:  1.5Å
Species:  SARS-CoV-2
References:  6
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of SARS-CoV 3C-like protease in apo form
PDB Id:  3VB3
Resolution:  2.2Å
Species:  SARS-CoV
References:  4
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of SARS coronavirus 3CL protease inhibitor complex
PDB Id:  2GX4
Ligand:  TG-0205221
Resolution:  1.93Å
Species:  SARS-CoV
References:  19
Image of receptor 3D structure from RCSB PDB
Description:  Covalent complex of SARS-CoV main protease with N-[(2S)-1-({(2S,3S)-3,4-dihydroxy-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl}amino)-4-methyl-1-oxopentan-2-yl]-4-methoxy-1H-indole-2-carboxamide
PDB Id:  6XHL
Ligand:  PF-00835231
Resolution:  1.47Å
Species:  SARS-CoV
References:  8
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of SARS-CoV-2 main protease in complex with MI-23
PDB Id:  7D3I
Ligand:  MI-23
Resolution:  2.0Å
Species:  SARS-CoV-2
References:  13
EC number (SARS-CoV-2)
3.4.22.69

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
PF-00835231 Small molecule or natural product Ligand has a PDB structure SARS-CoV Inhibition 8.4 pKi 8
⤷ pKi 8.4 (Ki 4x10-9 M) [8]
Description: Determined using an in vitro SARS-CoV-1 3CLpro FRET assay.
compound 17 [PMID: 33655614] Small molecule or natural product SARS-CoV-2 Inhibition 8.0 pKi 3
⤷ pKi 8.0 (Ki 1x10-8 M) [3]
compound 8 [PMID: 33655614] Small molecule or natural product SARS-CoV-2 Inhibition 7.6 pKi 3
⤷ pKi 7.6 (Ki 2.4x10-8 M) [3]
TG-0205221 Peptide Ligand has a PDB structure SARS-CoV Inhibition 7.3 pKi 19
⤷ pKi 7.3 (Ki 5.3x10-8 M) [19]
TG-0203770 Small molecule or natural product Ligand has a PDB structure SARS-CoV Inhibition 7.2 pKi 10
⤷ pKi 7.2 (Ki 5.8x10-8 M) [10]
boceprevir Small molecule or natural product Approved drug SARS-CoV-2 Inhibition 5.9 pKi 11
⤷ pKi 5.9 (Ki 1.18x10-6 M) [11]
Description: Inhibition of recombinat enzyme in vitro.
MI-23 Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 8.1 pIC50 13
⤷ pIC50 8.1 (IC50 7.6x10-9 M) [13]
Description: Inhibition of recombinant enzyme in vitro
MI-09 Small molecule or natural product SARS-CoV-2 Inhibition 7.8 pIC50 13
⤷ pIC50 7.8 (IC50 1.52x10-8 M) [13]
Description: Inhibition of recombinant enzyme in vitro
MI-30 Small molecule or natural product SARS-CoV-2 Inhibition 7.8 pIC50 13
⤷ pIC50 7.8 (IC50 1.72x10-8 M) [13]
Description: Inhibition of recombinant enzyme in vitro
GC-376 Small molecule or natural product SARS-CoV-2 Inhibition 7.5 pIC50 11
⤷ pIC50 7.5 (IC50 3x10-8 M) [11]
ALP-POS-c59291d4-5 Small molecule or natural product SARS-CoV Inhibition 7.5 pIC50 7
⤷ pIC50 7.5 (IC50 3x10-8 M) [7]
MP13 Small molecule or natural product SARS-CoV-2 Inhibition 7.5 pIC50 18
⤷ pIC50 7.5 (IC50 3.3x10-8 M) [18]
example 4 [WO2017114509] Small molecule or natural product SARS-CoV-2 Inhibition 7.5 pIC50 5
⤷ pIC50 7.5 (IC50 3.4x10-8 M) [5]
ML1000 Small molecule or natural product SARS-CoV-2 Inhibition 7.5 pIC50 16
⤷ pIC50 7.5 (IC50 3.4x10-8 M) [16]
compound 11b [PMID: 32321856] Small molecule or natural product SARS-CoV-2 Inhibition 7.4 pIC50 6
⤷ pIC50 7.4 (IC50 4x10-8 M) [6]
Description: In vitro inhibition of recombinant SARS-CoV-2 Mpro enzymatic activity.
ALP-POS-c59291d4-5 Small molecule or natural product SARS-CoV-2 Inhibition 7.3 pIC50 12
⤷ pIC50 7.3 (IC50 5x10-8 M) [12]
compound 11a [PMID: 32321856] Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 7.3 pIC50 6
⤷ pIC50 7.3 (IC50 5.3x10-8 M) [6]
Description: In vitro inhibition of recombinant SARS-CoV-2 Mpro enzymatic activity.
compound 5 [Zhang et al., 2021] Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 6.8 pIC50 20
⤷ pIC50 6.8 (IC50 1.4x10-7 M) [20]
compound 6e [PMID: 32747425] Small molecule or natural product SARS-CoV-2 Inhibition 6.8 pIC50 14
⤷ pIC50 6.8 (IC50 1.7x10-7 M) [14]
compound 11r [PMID: 32045235] Small molecule or natural product SARS-CoV-2 Inhibition 6.7 pIC50 22
⤷ pIC50 6.7 (IC50 1.8x10-7 M) [22]
walrycin B Small molecule or natural product SARS-CoV-2 Inhibition 6.6 pIC50 24
⤷ pIC50 6.6 (IC50 2.6x10-7 M) [24]
Description: Inhibition determined in an HTS fluorogenic enzyme activity assay.
DAV-CRI-14a23e73-1 Small molecule or natural product SARS-CoV-2 Inhibition 6.3 pIC50 12
⤷ pIC50 6.3 (IC50 4.7x10-7 M) [12]
compound 6j [PMID: 32747425] Small molecule or natural product SARS-CoV-2 Inhibition 6.3 pIC50 14
⤷ pIC50 6.3 (IC50 4.8x10-7 M) [14]
compound 13b [PMID: 32198291] Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 6.2 pIC50 22
⤷ pIC50 6.2 (IC50 6.7x10-7 M) [22]
compound 6e [PMID: 32747425] Small molecule or natural product SARS-CoV Inhibition 6.1 pIC50 14
⤷ pIC50 6.1 (IC50 9x10-7 M) [14]
compound 6j [PMID: 32747425] Small molecule or natural product SARS-CoV Inhibition 5.9 pIC50 14
⤷ pIC50 5.9 (IC50 1.2x10-6 M) [14]
boceprevir Small molecule or natural product Approved drug SARS-CoV Inhibition 5.6 – 6.0 pIC50 1-2
⤷ pIC50 5.6 – 6.0 (IC50 2.5x10-6 – 9.49x10-7 M) [1-2]
PRD_002214 Small molecule or natural product SARS-CoV Inhibition 5.1 pIC50 17
⤷ pIC50 5.1 (IC50 9x10-6 M) [17]
Z-FA-FMK Peptide Immunopharmacology Ligand SARS-CoV-2 Inhibition 4.9 pIC50 24
⤷ pIC50 4.9 (IC50 1.139x10-5 M) [24]
Description: Inhibition determined in an HTS fluorogenic enzyme activity assay.
PRD_002214 Small molecule or natural product SARS-CoV-2 Irreversible inhibition - - 9
⤷ [9]
View species-specific inhibitor tables
Inhibitor Comments
PRD_002214 (N3) inhibits SARS-CoV-2 plaque formation in Vero cell culture with an IC50 of 16.77 μM [9].
The MERS-CoV inhibitor compound 11r [PMID: 32045235] is active against SARS-CoV-2 [21].
Baker et al. (2021) performed a large scale repurposing screen, which corroborated the inhibitory activity of boceprevir (and other hepatitis C NS3/4A protease inhibitors) against SARS-CoV-2 Mpro [2].
General Comments
The coronavirus (CoV) main proteases (Mpro) are cysteine proteases that are encoded in the viral RNA replicase gene. Mpro catalyses the proteolytic processing (cleavage) of replicase precursor polyproteins in to discrete functional proteins. In total There are 11 Mpro cleavage site within the C-terminus of the replicase polyprotein. Mpro plays a central role in the viral life cycle, and in light of evidence from other coronaviruses, SARS-CoV Mpro was a lead target for antiviral drug discovery. Many of the compounds that were discovered to inhibit the activity of MERS- and SARS-CoV Mpro enzymes have been tested for activity against SARS-CoV-2 [15].

Although Mpro is strictly a component of the CoV replicase polyprotein(s) 1a and 1ab, we have included it as a separate entity to allow us to more sensibly curate pharmacological information (particularly regarding inhibitor development) that is specific for this protease, and to facilitate data retrieval.

References

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1. Anson BJ, Chapman ME, Lendy EK, Pshenychnyi S, D’Aquila RT, Satchell KJF, Mesecar AD. (2020) Broad-spectrum inhibition of coronavirus main and papain-like proteases by HCV drugs. Nature Research, PrePrint, Under Review. DOI: 10.21203/rs.3.rs-26344/v1

2. Baker JD, Uhrich RL, Kraemer GC, Love JE, Kraemer BC. (2021) A drug repurposing screen identifies hepatitis C antivirals as inhibitors of the SARS-CoV2 main protease. PLoS One, 16 (2): e0245962. [PMID:33524017]

3. Breidenbach J, Lemke C, Pillaiyar T, Schäkel L, Al Hamwi G, Diett M, Gedschold R, Geiger N, Lopez V, Mirza S et al.. (2021) Targeting the Main Protease of SARS-CoV-2: From the Establishment of High Throughput Screening to the Design of Tailored Inhibitors. Angew Chem Int Ed Engl, [Epub ahead of print]. DOI: 0.1002/anie.202016961 [PMID:33655614]

4. Chuck CP, Chen C, Ke Z, Wan DC, Chow HF, Wong KB. (2013) Design, synthesis and crystallographic analysis of nitrile-based broad-spectrum peptidomimetic inhibitors for coronavirus 3C-like proteases. Eur J Med Chem, 59: 1-6. [PMID:23202846]

5. Dai W, Jochmans D, Xie H, Yang H, Li J, Su H, Chang D, Wang J, Peng J, Zhu L et al.. (2021) Design, Synthesis, and Biological Evaluation of Peptidomimetic Aldehydes as Broad-Spectrum Inhibitors against Enterovirus and SARS-CoV-2. J Med Chem, [Epub ahead of print]. DOI: 10.1021/acs.jmedchem.0c02258 [PMID:33872498]

6. Dai W, Zhang B, Jiang XM, Su H, Li J, Zhao Y, Xie X, Jin Z, Peng J, Liu F et al.. (2020) Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease. Science, 368 (6497): 1331-1335. [PMID:32321856]

7. Ghosh AK, Gong G, Grum-Tokars V, Mulhearn DC, Baker SC, Coughlin M, Prabhakar BS, Sleeman K, Johnson ME, Mesecar AD. (2008) Design, synthesis and antiviral efficacy of a series of potent chloropyridyl ester-derived SARS-CoV 3CLpro inhibitors. Bioorg Med Chem Lett, 18 (20): 5684-8. [PMID:18796354]

8. Hoffman RL, Kania RS, Brothers MA, Davies JF, Ferre RA, Gajiwala KS, He M, Hogan RJ, Kozminski K, Li LY et al.. (2020) Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of COVID-19. J Med Chem, 63 (21): 12725-12747. [PMID:33054210]

9. Jin Z, Du X, Xu Y, Deng Y, Liu M, Zhang B, Li X, Zhang L, Peng C, Duan Y. (2020) Structure of Mpro from COVID-19 virus and discovery of its inhibitors. bioRxiv, Preprint. DOI: 10.1101/2020.02.26.964882

10. Lee CC, Kuo CJ, Ko TP, Hsu MF, Tsui YC, Chang SC, Yang S, Chen SJ, Chen HC, Hsu MC et al.. (2009) Structural basis of inhibition specificities of 3C and 3C-like proteases by zinc-coordinating and peptidomimetic compounds. J Biol Chem, 284 (12): 7646-55. [PMID:19144641]

11. Ma C, Sacco MD, Hurst B, Townsend JA, Hu Y, Szeto T, Zhang X, Tarbet B, Marty MT, Chen Y et al.. (2020) Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease. Cell Res, 30 (8): 678-692. DOI: 10.1038/s41422-020-0356-z [PMID:32541865]

12. PostEra AI. MPro Activity Data. Accessed on 11/08/2020. Modified on 11/08/2020. postera.ai/covid/activity_data, https://postera.ai/covid/activity_data

13. Qiao J, Li YS, Zeng R, Liu FL, Luo RH, Huang C, Wang YF, Zhang J, Quan B, Shen C et al.. (2021) SARS-CoV-2 Mpro inhibitors with antiviral activity in a transgenic mouse model. Science, [Epub ahead of print]. [PMID:33602867]

14. Rathnayake AD, Zheng J, Kim Y, Perera KD, Mackin S, Meyerholz DK, Kashipathy MM, Battaile KP, Lovell S, Perlman S et al.. (2020) 3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV-infected mice. Sci Transl Med, 12 (557). DOI: 10.1126/scitranslmed.abc5332 [PMID:32747425]

15. Riva L, Yuan S, Yin X, Martin-Sancho L, Matsunaga N, Pache L, Burgstaller-Muehlbacher S, De Jesus PD, Teriete P, Hull MV et al.. (2020) Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing. Nature, [Epub ahead of print]. DOI: 10.1038/s41586-020-2577-1

16. Westberg M, Su Y, Zou X, Ning L, Hurst B, Tarbet B, Lin MZ. (2021) Rational design of a new class of protease inhibitors for the potential treatment of coronavirus diseases. bioRxiv, Preprint. DOI: 10.1101/2020.09.15.275891

17. Yang H, Xie W, Xue X, Yang K, Ma J, Liang W, Zhao Q, Zhou Z, Pei D, Ziebuhr J et al.. (2005) Design of wide-spectrum inhibitors targeting coronavirus main proteases. PLoS Biol, 3 (10): e324. [PMID:16128623]

18. Yang KS, Ma XR, Ma Y, Alugubelli YR, Scott DA, Vatansever EC, Drelich AK, Sankaran B, Geng ZZ, Blankenship LR et al.. (2020) A Speedy Route to Multiple Highly Potent SARS-CoV-2 Main Protease Inhibitors. bioRxiv, Preprint. DOI: 10.1101/2020.07.28.223784 [PMID:32766582]

19. Yang S, Chen SJ, Hsu MF, Wu JD, Tseng CT, Liu YF, Chen HC, Kuo CW, Wu CS, Chang LW et al.. (2006) Synthesis, crystal structure, structure-activity relationships, and antiviral activity of a potent SARS coronavirus 3CL protease inhibitor. J Med Chem, 49 (16): 4971-80. [PMID:16884309]

20. Zhang C-H, Stone EA, Deshmukh M, Ippolito JA, Ghahremanpour MM, Tirado-Rives J, Spasov KA, Zhang S, Takeo Y, Kudalkar SN et al.. (2021) Potent Noncovalent Inhibitors of the Main Protease of SARS-CoV-2 from Molecular Sculpting of the Drug Perampanel Guided by Free Energy Perturbation Calculations. ACS Central Science,. DOI: 10.1021/acscentsci.1c00039

21. Zhang L, Lin D, Kusov Y, Nian Y, Ma Q, Wang J, von Brunn A, Leyssen P, Lanko K, Neyts J et al.. (2020) α-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment. J Med Chem, 63 (9): 4562-4578. [PMID:32045235]

22. Zhang L, Lin D, Sun X, Curth U, Drosten C, Sauerhering L, Backer S, Rox K, Hilgenfeld R. (2020) Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science,. DOI: 10.1126/science.abb3405

23. Zhang L, Lin D, Sun X, Curth U, Drosten C, Sauerhering L, Becker S, Rox K, Hilgenfeld R. (2020) Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science, 368 (6489): 409-412. [PMID:32198291]

24. Zhu W, Xu M, Chen CZ, Guo H, Shen M, Hu X, Shinn P, Klumpp-Thomas C, Michael SG, Zheng W. (2020) Identification of SARS-CoV-2 3CL Protease Inhibitors by a Quantitative High-throughput Screening. ACS Pharmacol Transl Sci, [Epub ahead of print]. DOI: 10.1021/acsptsci.0c00108

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