SARS-CoV-2 Main protease | SARS-CoV-2 proteins | IUPHAR/BPS Guide to PHARMACOLOGY

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SARS-CoV-2 Main protease

Target not currently curated in GtoImmuPdb

Target id: 3111

Nomenclature: SARS-CoV-2 Main protease

Family: SARS-CoV-2 proteins

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Contents:

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
SARS-CoV-2 - 306
Gene and Protein Information Comments
The SARS-CoV-2 main protease (Mpro) is a 306 amino acid cysteine protease that is encoded in the viral RNA replicase gene. The provisional RefSeq YP_009725301 has been 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 [2]. 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). Mpro is amino acids 3264-3569 of the full length polyprotein. We will include further reference information as it becomes available.
Previous and Unofficial Names
3c-like proteinase | SARS-CoV-2 Mpro | Chain A, 3c-like Proteinase | 3CL protease | Mpro | nsp5
Database Links
RefSeq Protein
Selected 3D Structures
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:  6
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:  2

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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
boceprevir CoV2 Inhibition 5.9 pKi 3
⤷ pKi 5.9 (Ki 1.18x10-6 M) [3]
Description: Inhibition of recombinat enzyme in vitro.
GC-376 CoV2 Inhibition 7.5 pIC50 3
⤷ pIC50 7.5 (IC50 3x10-8 M) [3]
compound 11r [PMID: 32045235] CoV2 Inhibition 6.7 pIC50 5
⤷ pIC50 6.7 (IC50 1.8x10-7 M) [5]
compound 13b [PMID: 32198291] CoV2 Inhibition 6.2 pIC50 5
⤷ pIC50 6.2 (IC50 6.7x10-7 M) [5]
boceprevir CoV2 Inhibition 5.6 pIC50 1
⤷ pIC50 5.6 (IC50 2.5x10-6 M) [1]
PRD_002214 CoV2 Irreversible inhibition - - 2
⤷ [2]
Inhibitor Comments
PRD_002214 (N3) inhibits SARS-CoV-2 plaque formation in Vero cell culture with an IC50 of 16.77 μM [2].
The MERS-CoV inhibitor compound 11r [PMID: 32045235] may have activity towards SARS-CoV-2 [4].
General Comments
The SARS-CoV-2 main protease (Mpro) is a 306 amino acid cysteine protease that is encoded in the viral RNA replicase gene. Mpro catalyses the proteolytic processing (cleavage) of replicase precursor polyproteins in to discrete functional proteins, so is pivotal for viral gene expression and replication. As such a crucial enzyme, Mpro is the target of drug-discovery efforts to identify selective inhibitors that could offer therapeutic anti-SARS-CoV-2 potential.

Although Mpro is strictly a component of the SARS-CoV-2 replicase polyprotein(s) 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.

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. 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

3. Ma C, Sacco MD, Hurst B,Townsend JA, Hu Y, Szeto T, Zhang X, Tarbet B, Marty MT, Y Chen Y, Wang J. (2020) Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease. bioRxiv, PrePrint. DOI: 10.1101/2020.04.20.051581

4. 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]

5. 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

6. 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]

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