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Gene and Protein Information  |
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| 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 [47]. 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. |
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| Previous and Unofficial Names |
| 3c-like proteinase | SARS-CoV-2 Mpro | Chain A, 3c-like Proteinase | 3CL protease | Mpro | nsp5 |
| Database Links |
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| ChEMBL Target | CHEMBL3927 (SARS-CoV) |
| RefSeq Protein | YP_009725301 (SARS-CoV-2) |
| UniProtKB | P0C6U8 (SARS-CoV) |
| Selected 3D Structures |
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| EC number (SARS-CoV-2) |
| 3.4.22.69 |
Download all structure-activity data for this target as a CSV file 
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| PRD_002214 (N3) inhibits SARS-CoV-2 plaque formation in Vero cell culture with an IC50 of 16.77 μM [47]. The MERS-CoV inhibitor compound 11r [PMID: 32045235] is active against SARS-CoV-2 [101]. 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 [5]. Chia et al. published a review of patents claiming coronavirus 3CLpro inhibitors in October 2021 [15]. |
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| Other Binding Ligands | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| General Comments |
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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 [73]. Inhibitor design and development in response to SARS-CoV-2 has been intense [50]. 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) [90]. 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. |
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2. 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
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4. Bai B, Belovodskiy A, Hena M, Kandadai AS, Joyce MA, Saffran HA, Shields JA, Khan MB, Arutyunova E, Lu J et al.. (2022) 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, 65 (4): 2905-2925. [PMID:34242027]
5. 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]
6. Boby ML, Fearon D, Ferla M, Filep M, Koekemoer L, Robinson MC, COVID Moonshot Consortium‡, Chodera JD, Lee AA, London N et al.. (2023) Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors. Science, 382 (6671): eabo7201. [PMID:37943932]
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11. Chakraborty S, Mallick D, Goswami M, Guengerich FP, Chakrabarty A, Chowdhury G. (2022) The Natural Products Withaferin A and Withanone from the Medicinal Herb Withania somnifera Are Covalent Inhibitors of the SARS-CoV-2 Main Protease. J Nat Prod, 85 (10): 2340-2350. [PMID:36098617]
12. Chamakuri S, Lu S, Ucisik MN, Bohren KM, Chen YC, Du HC, Faver JC, Jimmidi R, Li F, Li JY et al.. (2021) DNA-encoded chemistry technology yields expedient access to SARS-CoV-2 Mpro inhibitors. Proc Natl Acad Sci U S A, 118 (36). DOI: 10.1073/pnas.2111172118 [PMID:34426525]
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14. Chen X, Huang X, Ma Q, Kuzmič P, Zhou B, Zhang S, Chen J, Xu J, Liu B, Jiang H et al.. (2024) Preclinical evaluation of the SARS-CoV-2 Mpro inhibitor RAY1216 shows improved pharmacokinetics compared with nirmatrelvir. Nat Microbiol, 9 (4): 1075-1088. [PMID:38553607]
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18. Cooper MS, Zhang L, Ibrahim M, Zhang K, Sun X, Röske J, Göhl M, Brönstrup M, Cowell JK, Sauerhering L et al.. (2022) Diastereomeric Resolution Yields Highly Potent Inhibitor of SARS-CoV-2 Main Protease. J Med Chem, 65 (19): 13328-13342. [PMID:36179320]
19. Cui J, Jia J. (2021) Discovery of juglone and its derivatives as potent SARS-CoV-2 main proteinase inhibitors. Eur J Med Chem, 225: 113789. [PMID:34438124]
20. Dai W, Jochmans D, Xie H, Yang H, Li J, Su H, Chang D, Wang J, Peng J, Zhu L et al.. (2022) Design, Synthesis, and Biological Evaluation of Peptidomimetic Aldehydes as Broad-Spectrum Inhibitors against Enterovirus and SARS-CoV-2. J Med Chem, 65 (4): 2794-2808. [PMID:33872498]
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22. Dampalla CS, Kim Y, Bickmeier N, Rathnayake AD, Nguyen HN, Zheng J, Kashipathy MM, Baird MA, Battaile KP, Lovell S et al.. (2021) Structure-Guided Design of Conformationally Constrained Cyclohexane Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 3CL Protease. J Med Chem, 64 (14): 10047-10058. [PMID:34213885]
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25. Dampalla CS, Rathnayake AD, Perera KD, Jesri AM, Nguyen HN, Miller MJ, Thurman HA, Zheng J, Kashipathy MM, Battaile KP et al.. (2021) Structure-Guided Design of Potent Inhibitors of SARS-CoV-2 3CL Protease: Structural, Biochemical, and Cell-Based Studies. J Med Chem, 64 (24): 17846-17865. [PMID:34865476]
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32. Geng ZZ, Atla S, Shaabani N, Vulupala V, Yang KS, Alugubelli YR, Khatua K, Chen PH, Xiao J, Blankenship LR et al.. (2023) A Systematic Survey of Reversibly Covalent Dipeptidyl Inhibitors of the SARS-CoV-2 Main Protease. J Med Chem, 66 (16): 11040-11055. [PMID:37561993]
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34. Ghosh AK, Raghavaiah J, Shahabi D, Yadav M, Anson BJ, Lendy EK, Hattori SI, Higashi-Kuwata N, Mitsuya H, Mesecar AD. (2021) Indole Chloropyridinyl Ester-Derived SARS-CoV-2 3CLpro Inhibitors: Enzyme Inhibition, Antiviral Efficacy, Structure-Activity Relationship, and X-ray Structural Studies. J Med Chem, 64 (19): 14702-14714. [PMID:34528437]
35. Glaser J, Sedova A, Galanie S, Kneller DW, Davidson RB, Maradzike E, Del Galdo S, Labbé A, Hsu DJ, Agarwal R et al.. (2022) Hit Expansion of a Noncovalent SARS-CoV-2 Main Protease Inhibitor. ACS Pharmacol Transl Sci, 5 (4): 255-265. [PMID:35434531]
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