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CoV 3C-like (main) protease

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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 (3264-3569 of the full length polyprotein). The RefSeq YP_009725301 was allocated to SARS-CoV-2 Mpro. The protein has been crystalised in complex with the inhibitor PRD_002214 (N3), and the structure was submitted to the RCSB Protein Databank with ID 6LU7 [32]. The UniProt ID P0DTD1 refers to the complete SARS-CoV-2 replicase polyprotein (length 7096 amino acids). Mpro has been assigned the IUBMB enzyme nomenclature identifier EC 3.4.22.69.
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 YP_009725301 (SARS-CoV-2)
UniProtKB P0C6U8 (SARS-CoV)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Structure of SARS-CoV-2 3CL protease in complex with inhibitor 10c
PDB Id:  7T49
Ligand:  compound 10c [PMID: 35638577]
Resolution:  1.75Å
Species:  SARS-CoV-2
References:  17
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:  76
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:  32
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:  bofutrelvir
Resolution:  1.5Å
Species:  SARS-CoV-2
References:  15
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:  11
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:  68
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:  29
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:  50
Image of receptor 3D structure from RCSB PDB
Description:  The crystal structure of SARS-CoV-2 Main Protease in complex with masitinib
PDB Id:  7JU7
Ligand:  masitinib
Resolution:  1.6Å
Species:  SARS-CoV-2
References:  20
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the SARS-CoV-2 (COVID-19) main protease in complex with inhibitor UAWJ9-36-3
PDB Id:  7lyi
Ligand:  UAWJ9-36-3
Resolution:  1.9Å
Species:  SARS-CoV-2
References:  65
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332
PDB Id:  7VH8
Ligand:  nirmatrelvir
Resolution:  1.59Å
Species:  SARS-CoV-2
References:  77
Image of receptor 3D structure from RCSB PDB
Description:  Structure of SARS-CoV2 3CL protease covalently bound to peptidomimetic inhibitor
PDB Id:  7MBI
Ligand:  compound 15l [PMID: 34242027]
Resolution:  2.15Å
Species:  SARS-CoV-2
References:  3
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the SARS-CoV-2 main protease (Omicron variant) in complex with SY110
PDB Id:  8HHU
Ligand:  SY110
Resolution:  2.26Å
Species:  SARS-CoV-2
References:  31
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
WU-04 Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 7.4 pKd 30
⤷ pKd 7.4 (Kd 3.7x10-8 M) [30]
Description: binding to SARS-CoV-2 Mpro
compound 19 [PMID: 35142215] Small molecule or natural product SARS-CoV-2 Inhibition 7.4 pKd 41
⤷ pKd 7.4 (Kd 3.8x10-8 M) [41]
Description: Binding affinity
nirmatrelvir Small molecule or natural product Approved drug Ligand has a PDB structure SARS-CoV-2 Inhibition 9.6 pKi 46
⤷ pKi 9.6 (Ki 2.71x10-10 M) [46]
Description: Determined in vitro, in a TR-FRET enzyme assay
PF-00835231 Small molecule or natural product Ligand has a PDB structure SARS-CoV Inhibition 8.4 pKi 29
⤷ pKi 8.4 (Ki 4x10-9 M) [29]
Description: Determined using an in vitro SARS-CoV-1 3CLpro FRET assay.
YH-53 Small molecule or natural product Ligand has a PDB structure SARS-CoV Inhibition 8.2 pKi 55
⤷ pKi 8.2 (Ki 6.3x10-9 M) [55]
example 10 [WO2022129953] Small molecule or natural product SARS-CoV-2 Inhibition 8.2 pKi 12
⤷ pKi 8.2 (Ki 6.3x10-9 M) [12]
compound 17 [PMID: 33655614] Small molecule or natural product SARS-CoV-2 Inhibition 8.0 pKi 6
⤷ pKi 8.0 (Ki 1x10-8 M) [6]
compound 8 [PMID: 33655614] Small molecule or natural product SARS-CoV-2 Inhibition 7.6 pKi 6
⤷ pKi 7.6 (Ki 2.4x10-8 M) [6]
YH-53 Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 7.5 – 7.8 pKi 23,27,33
⤷ pKi 7.8 (Ki 1.76x10-8 M) [23,27]
pKi 7.5 (Ki 3.47x10-8 M) [33]
CDD-1976 Small molecule or natural product SARS-CoV-2 Inhibition 7.4 pKi 8
⤷ pKi 7.4 (Ki 3.7x10-8 M) [8]
TG-0205221 Peptide Ligand has a PDB structure SARS-CoV Inhibition 7.3 pKi 68
⤷ pKi 7.3 (Ki 5.3x10-8 M) [68]
TG-0203770 Small molecule or natural product Ligand has a PDB structure SARS-CoV Inhibition 7.2 pKi 36
⤷ pKi 7.2 (Ki 5.8x10-8 M) [36]
compound 7d [PMID: 34528437] Small molecule or natural product SARS-CoV-2 Inhibition 7.1 pKi 23
⤷ pKi 7.1 (Ki 7.3x10-8 M) [23]
compound 3 [PMID: 16884309] Peptide SARS-CoV Inhibition 6.2 pKi 68
⤷ pKi 6.2 (Ki 6.6x10-7 M) [68]
boceprevir Small molecule or natural product Approved drug SARS-CoV-2 Inhibition 5.9 pKi 42
⤷ pKi 5.9 (Ki 1.18x10-6 M) [42]
Description: Inhibition of recombinat enzyme in vitro.
Z-AVLD-FMK Peptide SARS-CoV-2 Inhibition 9.1 pIC50 43
⤷ pIC50 9.1 (IC50 8x10-10 M) [43]
Description: Inhibition in a FRET-based enzyme activity assay
compound 6 [WO2022133588] Small molecule or natural product SARS-CoV-2 Inhibition 9.0 pIC50 45
⤷ pIC50 9.0 (IC50 1x10-9 M) [45]
example 18 [WO2022013684] Small molecule or natural product SARS-CoV-2 Inhibition 8.8 pIC50 47
⤷ pIC50 8.8 (IC50 1.55x10-9 M) [47]
YH-6 Small molecule or natural product SARS-CoV-2 Inhibition 8.4 pIC50 28
⤷ pIC50 8.4 (IC50 3.8x10-9 M) [28]
compound 15g {PMID: 34242027] Small molecule or natural product SARS-CoV-2 Inhibition 8.2 pIC50 3
⤷ pIC50 8.2 (IC50 6.4x10-9 M) [3]
compound 17 [PMID: 33655614] Small molecule or natural product SARS-CoV Inhibition 8.1 pIC50 5
⤷ pIC50 8.1 (IC50 7x10-9 M) [5]
example 37 [WO2022021841A1] Small molecule or natural product SARS-CoV-2 Inhibition 8.1 pIC50
⤷ pIC50 8.1 (IC50 7x10-9 M)
Description: In vitro enzymatic activity inhibition
TKB245 Small molecule or natural product SARS-CoV-2 Inhibition 8.1 pIC50 44
⤷ pIC50 8.1 (IC50 7x10-9 M) [44]
Description: inhibition of enzyme activity
MI-23 Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 8.1 pIC50 50
⤷ pIC50 8.1 (IC50 7.6x10-9 M) [50]
Description: Inhibition of recombinant enzyme in vitro
MI-21 Small molecule or natural product SARS-CoV-2 Inhibition 8.1 pIC50 50
⤷ pIC50 8.1 (IC50 7.6x10-9 M) [50]
PF-00835231 Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 8.1 pIC50 61
⤷ pIC50 8.1 (IC50 8x10-9 M) [61]
TG-0205221 Peptide Ligand has a PDB structure SARS-CoV-2 Inhibition 8.1 pIC50 61
⤷ pIC50 8.1 (IC50 9x10-9 M) [61]
MI-28 Small molecule or natural product SARS-CoV-2 Inhibition 8.0 pIC50 50
⤷ pIC50 8.0 (IC50 9.2x10-9 M) [50]
UAWJ248 Small molecule or natural product SARS-CoV-2 Inhibition 7.9 pIC50 53
⤷ pIC50 7.9 (IC50 1.2x10-8 M) [53]
MI-13 Small molecule or natural product SARS-CoV-2 Inhibition 7.9 pIC50 50
⤷ pIC50 7.9 (IC50 1.24x10-8 M) [50]
ensitrelvir Small molecule or natural product Approved drug Ligand has a PDB structure SARS-CoV-2 Inhibition 7.9 pIC50 59
⤷ pIC50 7.9 (IC50 1.3x10-8 M) [59]
MI-14 Small molecule or natural product SARS-CoV-2 Inhibition 7.9 pIC50 50
⤷ pIC50 7.9 (IC50 1.3x10-8 M) [50]
3CL protease (Mpro) inhibitor M3 Small molecule or natural product SARS-CoV-2 Inhibition 7.9 pIC50 25
⤷ pIC50 7.9 (IC50 1.3x10-8 M) [25]
MI-05 Small molecule or natural product SARS-CoV-2 Inhibition 7.9 pIC50 50
⤷ pIC50 7.9 (IC50 1.32x10-8 M) [50]
MI-11 Small molecule or natural product SARS-CoV-2 Inhibition 7.9 pIC50 50
⤷ pIC50 7.9 (IC50 1.33x10-8 M) [50]
compound 15m [PMID: 34242027] Small molecule or natural product SARS-CoV-2 Inhibition 7.8 pIC50 3
⤷ pIC50 7.8 (IC50 1.4x10-8 M) [3]
SY110 Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 7.8 pIC50 31
⤷ pIC50 7.8 (IC50 1.44x10-8 M) [31]
MI-06 Small molecule or natural product SARS-CoV-2 Inhibition 7.8 pIC50 50
⤷ pIC50 7.8 (IC50 1.45x10-8 M) [50]
MI-09 Small molecule or natural product SARS-CoV-2 Inhibition 7.8 pIC50 50
⤷ pIC50 7.8 (IC50 1.52x10-8 M) [50]
Description: Inhibition of recombinant enzyme in vitro
NK01-63 Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 7.8 pIC50 39
⤷ pIC50 7.8 (IC50 1.6x10-8 M) [39]
MI-30 Small molecule or natural product SARS-CoV-2 Inhibition 7.8 pIC50 50
⤷ pIC50 7.8 (IC50 1.72x10-8 M) [50]
Description: Inhibition of recombinant enzyme in vitro
compound 15l [PMID: 34242027] Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 7.7 pIC50 3
⤷ pIC50 7.7 (IC50 1.9x10-8 M) [3]
Description: Inhibition of enzymatic activity in a FRET-based kinetic assay.
CCF981 Small molecule or natural product SARS-CoV Inhibition 7.7 pIC50 26
⤷ pIC50 7.7 (IC50 1.9x10-8 M) [26]
compound 21 [PMID: 33786375] Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 7.7 pIC50 73
⤷ pIC50 7.7 (IC50 1.9x10-8 M) [73]
compound 58 [WO2021252491A1] Small molecule or natural product SARS-CoV-2 Inhibition >7.7 pIC50 60
⤷ pIC50 >7.7 (IC50 <2x10-8 M) [60]
GDI-036 Small molecule or natural product SARS-CoV-2 Inhibition 7.7 pIC50 40
⤷ pIC50 7.7 (IC50 2x10-8 M) [40]
example 100 [WO2022043374] Small molecule or natural product SARS-CoV-2 Inhibition 7.6 pIC50 9
⤷ pIC50 7.6 (IC50 2.4x10-8 M) [9]
compound 23 [PMID: 33786375] Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 7.6 pIC50 73
⤷ pIC50 7.6 (IC50 2.4x10-8 M) [73]
nirmatrelvir Small molecule or natural product Approved drug Ligand has a PDB structure SARS-CoV-2 Inhibition 7.5 – 7.7 pIC50 41
⤷ pIC50 7.7 (IC50 1.9x10-8 M) Value provided at a session by Dafydd Owen (Pfizer) at the ACS Spring 2021 meeting; not yet published
pIC50 7.5 (IC50 3.3x10-8 M) [41]
bofutrelvir Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 7.3 – 7.8 pIC50 15,61
⤷ pIC50 7.8 (IC50 1.4x10-8 M) [61]
pIC50 7.3 (IC50 5.3x10-8 M) [15]
Description: In vitro inhibition of recombinant SARS-CoV-2 Mpro enzymatic activity.
compound 11b [PMID: 32321856] Small molecule or natural product SARS-CoV-2 Inhibition 7.4 – 7.6 pIC50 15,61
⤷ pIC50 7.6 (IC50 2.3x10-8 M) [61]
pIC50 7.4 (IC50 4x10-8 M) [15]
Description: In vitro inhibition of recombinant SARS-CoV-2 Mpro enzymatic activity.
GRL-0496 Small molecule or natural product SARS-CoV Inhibition 7.5 pIC50 22
⤷ pIC50 7.5 (IC50 3x10-8 M) [22]
example 100 [WO2022043374] Small molecule or natural product SARS-CoV Inhibition 7.5 pIC50 9
⤷ pIC50 7.5 (IC50 3.1x10-8 M) [9]
MP13 Small molecule or natural product SARS-CoV-2 Inhibition 7.5 pIC50 67
⤷ pIC50 7.5 (IC50 3.3x10-8 M) [67]
example 4 [WO2017114509] Small molecule or natural product SARS-CoV-2 Inhibition 7.5 pIC50 14
⤷ pIC50 7.5 (IC50 3.4x10-8 M) [14]
ML1000 Small molecule or natural product SARS-CoV-2 Inhibition 7.5 pIC50 64
⤷ pIC50 7.5 (IC50 3.4x10-8 M) [64]
compound 19 [PMID: 33786375] Small molecule or natural product SARS-CoV-2 Inhibition 7.4 pIC50 70
⤷ pIC50 7.4 (IC50 4.4x10-8 M) [70]
Description: Inhibition of Mpro proteolytic activity, determined using a substrate peptide cleavage FRET assay.
GC-376 Small molecule or natural product SARS-CoV Inhibition 7.3 – 7.4 pIC50 62,65
⤷ pIC50 7.4 (IC50 4.1x10-8 M) [65]
pIC50 7.3 (IC50 5x10-8 M) [62]
GRL-0496 Small molecule or natural product SARS-CoV-2 Inhibition 7.3 pIC50 49
⤷ pIC50 7.3 (IC50 5x10-8 M) [49]
compound 15c [PMID: 34865476] Small molecule or natural product MERS-CoV Inhibition 7.3 pIC50 18
⤷ pIC50 7.3 (IC50 5x10-8 M) [18]
UAWJ9-36-3 Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 7.3 pIC50 65
⤷ pIC50 7.3 (IC50 5.4x10-8 M) [65]
WU-04 Small molecule or natural product Ligand has a PDB structure SARS-CoV Inhibition 7.3 pIC50 30
⤷ pIC50 7.3 (IC50 5.5x10-8 M) [30]
Description: inhibition of SARS-CoV Mpro
example 45 [WO2022229458] Small molecule or natural product SARS-CoV-2 Inhibition 7.2 pIC50 7
⤷ pIC50 7.2 (IC50 5.7x10-8 M) [7]
compound 17 [PMID: 34408808] Small molecule or natural product SARS-CoV-2 Inhibition 7.2 pIC50 72
⤷ pIC50 7.2 (IC50 5.9x10-8 M) [72]
INSCoV-614 (1B) Small molecule or natural product SARS-CoV-2 Inhibition 7.2 pIC50 69
⤷ pIC50 7.2 (IC50 6x10-8 M) [69]
compound 21 [PMID: 34408808] Small molecule or natural product SARS-CoV-2 Inhibition 7.2 pIC50 70
⤷ pIC50 7.2 (IC50 6.1x10-8 M) [70]
Description: Inhibition of Mpro proteolytic activity, determined using a substrate peptide cleavage FRET assay.
compound 16 [PMID: 34408808] Small molecule or natural product SARS-CoV-2 Inhibition 7.2 pIC50 72
⤷ pIC50 7.2 (IC50 6.1x10-8 M) [72]
compound 21 [PMID: 34347470] Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 7.2 pIC50 26
⤷ pIC50 7.2 (IC50 6.3x10-8 M) [26]
compound 17 [PMID: 33655614] Small molecule or natural product SARS-CoV-2 Inhibition 7.2 pIC50 61
⤷ pIC50 7.2 (IC50 6.5x10-8 M) [61]
CCF981 Small molecule or natural product SARS-CoV-2 Inhibition 7.2 pIC50 26
⤷ pIC50 7.2 (IC50 6.8x10-8 M) [26]
GC-373 Peptide SARS-CoV Inhibition 7.2 pIC50 62
⤷ pIC50 7.2 (IC50 7x10-8 M) [62]
WU-04 Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 7.1 pIC50 30
⤷ pIC50 7.1 (IC50 7.2x10-8 M) [30]
Description: enzyme inhibition
compound 15 [PMID: 34438124] Small molecule or natural product SARS-CoV-2 Inhibition 7.1 pIC50 13
⤷ pIC50 7.1 (IC50 7.2x10-8 M) [13]
compound 19 [PMID: 35142215] Small molecule or natural product SARS-CoV-2 Inhibition 7.1 pIC50 41
⤷ pIC50 7.1 (IC50 7.7x10-8 M) [41]
Description: Inhibtion of protease activity
PET-UNK-29afea89-2 Small molecule or natural product SARS-CoV-2 Inhibition 7.1 pIC50 24
⤷ pIC50 7.1 (IC50 8x10-8 M) [24]
compound 2i [PMID: 23245752] Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 7.0 pIC50 61
⤷ pIC50 7.0 (IC50 9.4x10-8 M) [61]
UAWJ9-36-3 Small molecule or natural product Ligand has a PDB structure SARS-CoV Inhibition 7.0 pIC50 65
⤷ pIC50 7.0 (IC50 9.9x10-8 M) [65]
compound 19 [PMID: 34347470] Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 7.0 pIC50 26
⤷ pIC50 7.0 (IC50 1.06x10-7 M) [26]
compound 13 [PMID: 33984473] Small molecule or natural product SARS-CoV-2 Inhibition 7.0 pIC50 21
⤷ pIC50 7.0 (IC50 1.1x10-7 M) [21]
GC-376 Small molecule or natural product SARS-CoV-2 Inhibition 6.4 – 7.5 pIC50 19,41-42,62,65
⤷ pIC50 7.5 (IC50 3x10-8 M) [42]
pIC50 7.4 (IC50 4.1x10-8 M) [65]
pIC50 7.1 (IC50 7.3x10-8 M) [41]
pIC50 6.7 (IC50 1.9x10-7 M) [62]
pIC50 6.4 (IC50 4.1x10-7 M) [19]
GC-373 Peptide SARS-CoV-2 Inhibition 6.4 – 7.4 pIC50 61-62
⤷ pIC50 7.4 (IC50 4.2x10-8 M) [61]
pIC50 6.4 (IC50 4x10-7 M) [62]
compound 14 [PMID: 33786375] Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 6.9 pIC50 73
⤷ pIC50 6.9 (IC50 1.29x10-7 M) [73]
compound 5 [Zhang et al., 2021] Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 6.8 pIC50 71
⤷ pIC50 6.8 (IC50 1.4x10-7 M) [71]
compound 6e [PMID: 32747425] Small molecule or natural product SARS-CoV-2 Inhibition 6.8 pIC50 51
⤷ pIC50 6.8 (IC50 1.7x10-7 M) [51]
compound 15c [PMID: 34865476] Small molecule or natural product SARS-CoV-2 Inhibition 6.8 pIC50 18
⤷ pIC50 6.8 (IC50 1.7x10-7 M) [18]
compound 1 [PMID: 34210738] Small molecule or natural product SARS-CoV-2 Inhibition 6.8 pIC50 19
⤷ pIC50 6.8 (IC50 1.7x10-7 M) [19]
compound 40 [PMID: 34347470] Small molecule or natural product SARS-CoV-2 Inhibition 6.8 pIC50 26
⤷ pIC50 6.8 (IC50 1.71x10-7 M) [26]
compound 11r [PMID: 32045235] Small molecule or natural product SARS-CoV-2 Inhibition 6.7 pIC50 75
⤷ pIC50 6.7 (IC50 1.8x10-7 M) [75]
compound 2a [PMID: 34213885] Small molecule or natural product SARS-CoV-2 Inhibition 6.7 pIC50 16
⤷ pIC50 6.7 (IC50 1.8x10-7 M) [16]
Description: Determined in a FRET enzyme assay.
MAT-POS-932d1078-3 Small molecule or natural product SARS-CoV-2 Inhibition 6.7 pIC50 57
⤷ pIC50 6.7 (IC50 1.91x10-7 M) [57]
MAT-POS-b3e365b9-1 Small molecule or natural product SARS-CoV-2 Inhibition 6.7 pIC50 24
⤷ pIC50 6.7 (IC50 2x10-7 M) [24]
example I-1 [WO2023283831] Small molecule or natural product SARS-CoV-2 Inhibition >6.7 pIC50 54
⤷ pIC50 >6.7 (IC50 <2x10-7 M) [54]
compound 10c [PMID: 35638577] Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 6.6 pIC50 17
⤷ pIC50 6.6 (IC50 2.4x10-7 M) [17]
walrycin B Small molecule or natural product SARS-CoV-2 Inhibition 6.6 pIC50 78
⤷ pIC50 6.6 (IC50 2.6x10-7 M) [78]
Description: Inhibition determined in an HTS fluorogenic enzyme activity assay.
compound 3 [PMID: 16884309] Peptide SARS-CoV-2 Inhibition 6.5 pIC50 61
⤷ pIC50 6.5 (IC50 2.86x10-7 M) [61]
compound 10c [PMID: 35638577] Small molecule or natural product Ligand has a PDB structure MERS-CoV Inhibition 6.5 pIC50 17
⤷ pIC50 6.5 (IC50 3.3x10-7 M) [17]
DAV-CRI-14a23e73-1 Small molecule or natural product SARS-CoV-2 Inhibition 6.3 pIC50 49
⤷ pIC50 6.3 (IC50 4.7x10-7 M) [49]
compound 6j [PMID: 32747425] Small molecule or natural product SARS-CoV-2 Inhibition 6.3 pIC50 51
⤷ pIC50 6.3 (IC50 4.8x10-7 M) [51]
compound 13b [PMID: 32198291] Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 6.2 pIC50 75
⤷ pIC50 6.2 (IC50 6.7x10-7 M) [75]
compound 6e [PMID: 32747425] Small molecule or natural product SARS-CoV Inhibition 6.1 pIC50 51
⤷ pIC50 6.1 (IC50 9x10-7 M) [51]
WU-04 Small molecule or natural product Ligand has a PDB structure MERS-CoV Inhibition 6.0 pIC50
⤷ pIC50 6.0 (IC50 1.02x10-6 M)
Description: inhibition of MERS-CoV Mpro
compound 6j [PMID: 32747425] Small molecule or natural product SARS-CoV Inhibition 5.9 pIC50 51
⤷ pIC50 5.9 (IC50 1.2x10-6 M) [51]
boceprevir Small molecule or natural product Approved drug SARS-CoV Inhibition 5.6 – 6.0 pIC50 1,4
⤷ pIC50 5.6 – 6.0 (IC50 2.5x10-6 – 9.49x10-7 M) [1,4]
compound 2i [PMID: 23245752] Small molecule or natural product Ligand has a PDB structure SARS-CoV Inhibition 5.8 pIC50 34
⤷ pIC50 5.8 (IC50 1.7x10-6 M) [34]
MG-132 Peptide Ligand has a PDB structure SARS-CoV-2 Inhibition 5.4 pIC50 42
⤷ pIC50 5.4 (IC50 3.9x10-6 M) [42]
boceprevir Small molecule or natural product Approved drug SARS-CoV-2 Inhibition 5.4 pIC50 42
⤷ pIC50 5.4 (IC50 4.13x10-6 M) [42]
ML300 Small molecule or natural product Ligand has a PDB structure SARS-CoV Inhibition 5.3 – 5.4 pIC50 26,58
⤷ pIC50 5.4 (IC50 4.1x10-6 M) [58]
pIC50 5.3 (IC50 4.45x10-6 M) [26]
compound 451 [WO2021252644A1] Small molecule or natural product SARS-CoV-2 Inhibition 5.0 – 5.7 pIC50 2
⤷ pIC50 5.0 – 5.7 (IC50 1x10-5 – 2x10-6 M) [2]
Description: In vitro inhibition of Mpro; binned IC50 value
ML300 Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 5.3 pIC50 26
⤷ pIC50 5.3 (IC50 4.99x10-6 M) [26]
MG-115 Peptide SARS-CoV-2 Inhibition 5.2 pIC50 42
⤷ pIC50 5.2 (IC50 6.14x10-6 M) [42]
PRD_002214 Small molecule or natural product SARS-CoV Inhibition 5.1 pIC50 66
⤷ pIC50 5.1 (IC50 9x10-6 M) [66]
calpeptin Peptide SARS-CoV-2 Inhibition 5.0 pIC50 42
⤷ pIC50 5.0 (IC50 1.069x10-5 M) [42]
telaprevir Small molecule or natural product SARS-CoV-2 Inhibition 4.9 pIC50 48
⤷ pIC50 4.9 (IC50 1.147x10-5 M) [48]
Z-FA-FMK Peptide Immunopharmacology Ligand SARS-CoV-2 Inhibition 4.9 pIC50 78
⤷ pIC50 4.9 (IC50 1.139x10-5 M) [78]
Description: Inhibition determined in an HTS fluorogenic enzyme activity assay.
compound 25c [PMID: 23747811] Peptide SARS-CoV Inhibition 4.7 pIC50 56
⤷ pIC50 4.7 (IC50 2.1x10-5 M) [56]
PRD_002214 Small molecule or natural product SARS-CoV-2 Irreversible inhibition - - 32
⤷ [32]
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 [32].
The MERS-CoV inhibitor compound 11r [PMID: 32045235] is active against SARS-CoV-2 [74].
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 [4].
Chia et al. published a review of patents claiming coronavirus 3CLpro inhibitors in October 2021 [10].
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
CoV Mpro CRBN PROTAC 9 [US11530195] Small molecule or natural product SARS-CoV-2 Binding >7.0 pIC50 38
⤷ pIC50 >7.0 (IC50 <1x10-7 M) [38]
CoV Mpro VHL PROTAC 9 [US11518759] Small molecule or natural product SARS-CoV-2 Binding >7.0 pIC50 37
⤷ pIC50 >7.0 (IC50 <1x10-7 M) [37]
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 [52]. Inhibitor design and development in response to SARS-CoV-2 has been intense [35].

Mpro has been reported to induce damage to the microvascular network in the brain, via proteolytic cleavage and inactivation of the endothelially-expressed protein NEMO (an essential NF-κB modulator with a central role in immunity; HGNC symbol IKBKG) [63]. Depletion of NEMO leads to cell death, and this cell death is dependent on receptor-interacting protein kinase 3 (RIPK3) signalling. A small molecule inhibitor of RIPK1, an upstream kinase that activates RIPK3, was shown to block the Mpro-induced microvascular pathology. It is interesting to note that a RIPK1 inhibitor (SAR443122) is already under clinical evaluation in COVID-19 patients.

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. Arnold LD, Jennings A, Keung W. (2021) Inhibitors of cysteine proteases and methods of use thereof. Patent number: WO2021252644A1. Assignee: Pardes Biosciences, Inc.. Priority date: 09/06/2020. Publication date: 16/12/2021.

3. Bai B, Belovodskiy A, Hena M, Kandadai AS, Joyce MA, Saffran HA, Shields JA, Khan MB, Arutyunova E, Lu J et al.. (2021) Peptidomimetic α-Acyloxymethylketone Warheads with Six-Membered Lactam P1 Glutamine Mimic: SARS-CoV-2 3CL Protease Inhibition, Coronavirus Antiviral Activity, and in Vitro Biological Stability. J Med Chem, [Epub ahead of print]. DOI: 10.1021/acs.jmedchem.1c00616 [PMID:34242027]

4. 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]

5. Botyanszki J, Catalano G, Chong PY, Dickson H, Jin Q, Leivers A, Maynard A, Liao X, Miller J, Shotwell JB et al.. (2018) Compounds that inhibit 3c and 3cl proteases and methods of use thereof. Patent number: WO2018042343A2. Assignee: Glaxosmithkline Intellectual Property (No.2) Limited. Priority date: 30/08/2016. Publication date: 08/03/2018.

6. 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]

7. Carlsson J, Danielson H, Moodie L, Sandstrom A. (2022) SUBSTITUTED HYDANTOIN COMPOUNDS, METHODS FOR PREPARATION THEREOF AND USE THEREOF IN THE TREATMENT AND/OR PREVENTION OF A CORONA VIRUS DISEASE. Patent number: