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CoV Non-structural protein 14

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Target not currently curated in GtoImmuPdb

Target id: 3198

Nomenclature: CoV Non-structural protein 14

Family: Coronavirus (CoV) proteins

Previous and Unofficial Names Click here for help
(N7-guanine)-methyltransferase | N7-MTase
Database Links Click here for help
UniProtKB
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the SARS coronavirus nsp14-nsp10 complex with functional ligands SAH and GpppA
PDB Id:  5C8S
Ligand:  S-adenosylhomocysteine
Resolution:  3.3Å
Species:  SARS-CoV
References:  5

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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
TO507 Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Binding 7.6 pKd 9
pKd 7.6 (Kd 2.52x10-8 M) [9]
SS148 Small molecule or natural product Click here for species-specific activity table SARS-CoV-2 Binding 7.3 pKd 4
pKd 7.3 (Kd 5x10-8 M) [4]
NSC620333 Small molecule or natural product SARS-CoV-2 Inhibition 6.4 pKd 7
pKd 6.4 (Kd 4.27x10-7 M) [7]
TO507 Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 8.5 pIC50 9
pIC50 8.5 (IC50 3x10-9 M) [9]
Description: Inhibition of MTase activity
CoV nsp16 inhibitor 2a [PMID: 34257831] Small molecule or natural product Click here for species-specific activity table SARS-CoV-2 Inhibition 8.1 pIC50 2
pIC50 8.1 (IC50 8x10-9 M) [2]
compound 25 [PMID: 35439007] Small molecule or natural product SARS-CoV-2 Inhibition 7.7 pIC50 1
pIC50 7.7 (IC50 1.9x10-8 M) [1]
HK370 Small molecule or natural product SARS-CoV-2 Inhibition 7.5 pIC50 3
pIC50 7.5 (IC50 3.1x10-8 M) [3]
SS148 Small molecule or natural product Click here for species-specific activity table SARS-CoV-2 Inhibition 7.2 pIC50 4
pIC50 7.2 (IC50 7x10-8 M) [4]
'1988 Small molecule or natural product SARS-CoV-2 Inhibition 5.7 pIC50 10
pIC50 5.7 (IC50 2.2x10-6 M) [10]
NSC620333 Small molecule or natural product SARS-CoV-2 Inhibition 5.3 pIC50 7
pIC50 5.3 (IC50 5x10-6 M) [7]
Description: Inhibition of nsp14 MTase activity in a biochemical assay
'2882 Small molecule or natural product SARS-CoV-2 Inhibition 5.2 pIC50 10
pIC50 5.2 (IC50 6x10-6 M) [10]
'9213 Small molecule or natural product SARS-CoV-2 Inhibition 4.7 pIC50 10
pIC50 4.7 (IC50 2x10-5 M) [10]
General Comments
Nsp14 is a bifunctional enzyme. It is one of two nonstructural proteins that are encoded in the coronavirus RNA genome that have methyltransferase (MTase) activity [6,8,11]. Nsp16 is the other MTase. Nsp14's MTase activity resides in its C-terminal domain, and its N-terminal domain has 3'-to-5' exoribonuclease (ExoN) activity. The MTase activity catalyses the transfer of the methyl group from the S-adenosyl-l-methionine (SAM) cofactor to the N7-guanosine cap on the viral mRNA, yielding S-adenosyl-l-homocysteine (SAH) as a reaction product. Capping the RNA molecules is essential for viral mRNA stability and translation, and it helps the virus to evade the host's innate immune response. Based on evidence from SARS-CoV, ExoN function is proposed to provide a proofreading mechanism during genome replication [6]. Further experimental investigation indicates that nsp10 interacts with nsp14 to form the active proofreading exonuclease assembly [...].

SAM/SAH derivatives that act as nsp14 inhibitors are being explored for antiviral activity against SARS-CoV-2 (and other related coronaviruses) [1,9].

References

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1. Ahmed-Belkacem R, Hausdorff M, Delpal A, Sutto-Ortiz P, Colmant AMG, Touret F, Ogando NS, Snijder EJ, Canard B, Coutard B et al.. (2022) Potent Inhibition of SARS-CoV-2 nsp14 N7-Methyltransferase by Sulfonamide-Based Bisubstrate Analogues. J Med Chem, 65 (8): 6231-6249. [PMID:35439007]

2. Bobiļeva O, Bobrovs R, Kaņepe I, Patetko L, Kalniņš G, Šišovs M, Bula AL, Gri Nberga S, Borodušķis MR, Ramata-Stunda A et al.. (2021) Potent SARS-CoV-2 mRNA Cap Methyltransferase Inhibitors by Bioisosteric Replacement of Methionine in SAM Cosubstrate. ACS Med Chem Lett, 12 (7): 1102-1107. [PMID:34257831]

3. Kocek H, Chalupská D, Dejmek M, Dvořáková A, Zgarbová M, Šála M, Chalupský K, Krafčíková P, Otava T, Drexler M et al.. (2024) Discovery of highly potent SARS-CoV-2 nsp14 methyltransferase inhibitors based on adenosine 5'-carboxamides. RSC Med Chem, 15 (10): 3469-76 [Epub ahead of print]. [PMID:39220762]

4. Li X, Song Y. (2024) Perspective for Drug Discovery Targeting SARS Coronavirus Methyltransferases: Function, Structure and Inhibition. J Med Chem, 67 (21): 18642-18655. [PMID:39478665]

5. Ma Y, Wu L, Shaw N, Gao Y, Wang J, Sun Y, Lou Z, Yan L, Zhang R, Rao Z. (2015) Structural basis and functional analysis of the SARS coronavirus nsp14-nsp10 complex. Proc Natl Acad Sci U S A, 112 (30): 9436-41. [PMID:26159422]

6. Minskaia E, Hertzig T, Gorbalenya AE, Campanacci V, Cambillau C, Canard B, Ziebuhr J. (2006) Discovery of an RNA virus 3'->5' exoribonuclease that is critically involved in coronavirus RNA synthesis. Proc Natl Acad Sci USA, 103 (13): 5108-13. [PMID:16549795]

7. Nigam AK, Hurley MFD, Fengling Li F, Konkoľová E, Klíma M, Trylčová J, Pollice R, Çinaroǧlu SS, Levin-Konigsberg R, Handjaya J et al.. (2024) Application of established computational techniques to identify potential SARS-CoV-2 Nsp14-MTase inhibitors in low data regimes. Digital Discovery, 3 (7): 1327-1341. DOI: 10.1039/D4DD00006D

8. Ogando NS, Zevenhoven-Dobbe JC, van der Meer Y, Bredenbeek PJ, Posthuma CC, Snijder EJ. (2020) The Enzymatic Activity of the nsp14 Exoribonuclease Is Critical for Replication of MERS-CoV and SARS-CoV-2. J Virol, 94 (23). DOI: 10.1128/JVI.01246-20 [PMID:32938769]

9. Otava T, Šála M, Li F, Fanfrlík J, Devkota K, Perveen S, Chau I, Pakarian P, Hobza P, Vedadi M et al.. (2021) The Structure-Based Design of SARS-CoV-2 nsp14 Methyltransferase Ligands Yields Nanomolar Inhibitors. ACS Infect Dis, 7 (8): 2214-2220. [PMID:34152728]

10. Singh I, Li F, Fink EA, Chau I, Li A, Rodriguez-Hernández A, Glenn I, Zapatero-Belinchón FJ, Rodriguez ML, Devkota K et al.. (2023) Structure-Based Discovery of Inhibitors of the SARS-CoV-2 Nsp14 N7-Methyltransferase. J Med Chem,. DOI: 10.1021/acs.jmedchem.2c02120

11. Snijder EJ, Decroly E, Ziebuhr J. (2016) The Nonstructural Proteins Directing Coronavirus RNA Synthesis and Processing. Adv Virus Res, 96: 59-126. [PMID:27712628]

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