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CoV RNA-dependent RNA polymerase

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Target not currently curated in GtoImmuPdb

Target id: 3139

Nomenclature: CoV RNA-dependent RNA polymerase

Family: Coronavirus (CoV) proteins

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Gene and Protein Information Comments
SARS-CoV RdRp is a 932 amino acid protein that is amino acids 4370-5301 of the polyprotein encoded by Orf1b.
SARS-CoV-2 RdRp is a 932 amino acid protein that is amino acids 4393-5324 of the polyprotein encoded by Orf1b.
Previous and Unofficial Names Click here for help
non-structural protein 12 | nsp12
Database Links Click here for help
ChEMBL Target
UniProtKB
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  SARS-Cov-2 RNA-dependent RNA polymerase in complex with cofactors
PDB Id:  6M71
Resolution:  2.9Å
Species:  SARS-CoV-2
References:  1
Image of receptor 3D structure from RCSB PDB
Description:  The nsp12-nsp7-nsp8 complex bound to the template-primer RNA and triphosphate form of Remdesivir(RTP)
PDB Id:  7BV2
Ligand:  remdesivir triphosphate
Resolution:  2.5Å
Species:  SARS-CoV-2
References:  8

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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
remdesivir Small molecule or natural product Approved drug SARS-CoV-2 Inhibition - - 2
[2]
remdesivir Small molecule or natural product Approved drug Click here for species-specific activity table SARS-CoV Inhibition - - 2
[2]
GS-621763 Small molecule or natural product SARS-CoV-2 Inhibition - - 6
[6]
View species-specific inhibitor tables
General Comments
Coronavirus RdRp is a highly investigated molecular target for antiviral drug development [3,7,9], and is the target of the much publicised drug remdesivir. Although RdRp (nsp12) is strictly a component of the SARS-CoV-2 replicase polyprotein 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 enzyme. RdRp functions as a component of a genome replication protein complex that also contains nsp7 and nsp8 [4-5]. RdRp-mediated replication can be primer-dependent, but RdRp is also capable of de novo (primer-independent) RNA synthesis [4]. Because of the conserved structure of the key drug-binding pockets between SARS-CoV-2, SARS-CoV, and MERS-CoV RdRps, redeploying known SARS-CoV and MERS-CoV inhibitors for SARS-CoV-2 is an obvious strategy to combat SARS-CoV-2. To enhance therapeutic efficacy a sensible strategy would be to develop a multi-targeted combination of RdRp inhibitors with approved or clinical-stage drug candidates against other viral and/or host proteins.

References

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1. Gao Y, Yan L, Huang Y, Liu F, Zhao Y, Cao L, Wang T, Sun Q, Ming Z, Zhang L et al.. (2020) Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science, 368 (6492): 779-782. [PMID:32277040]

2. Gordon CJ, Tchesnokov EP, Woolner E, Perry JK, Feng JY, Porter DP, Götte M. (2020) Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency. J Biol Chem, 295 (20): 6785-6797. [PMID:32284326]

3. Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, O'Meara MJ, Rezelj VV, Guo JZ, Swaney DL et al.. (2020) A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature, 583 (7816): 459-468. [PMID:32353859]

4. Imbert I, Guillemot JC, Bourhis JM, Bussetta C, Coutard B, Egloff MP, Ferron F, Gorbalenya AE, Canard B. (2006) A second, non-canonical RNA-dependent RNA polymerase in SARS coronavirus. EMBO J, 25 (20): 4933-42. [PMID:17024178]

5. Kirchdoerfer RN, Ward AB. (2019) Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 co-factors. Nat Commun, 10 (1): 2342. [PMID:31138817]

6. Schäfer A, Martinez DR, Won JJ, Moreira FR, Brown AJ, Gully KL, Kalla R, Chun K, Du Pont V, Babusis D et al.. (2021) Therapeutic efficacy of an oral nucleoside analog of remdesivir against SARS-CoV-2 pathogenesis in mice. bioRxiv, Preprint. DOI: 10.1101/2021.09.13.460111 [PMID:34545367]

7. Shahid M, Shahzad-Ul-Hussan S. (2020) Structural insights of key enzymes into therapeutic intervention against SARS-CoV-2. J Struct Biol, 213 (1): 107690 [Epub ahead of print]. [PMID:33383190]

8. Yin W, Mao C, Luan X, Shen DD, Shen Q, Su H, Wang X, Zhou F, Zhao W, Gao M et al.. (2020) Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir. Science, 368 (6498): 1499-1504. [PMID:32358203]

9. Zhu W, Chen CZ, Gorshkov K, Xu M, Lo DC, Zheng W. (2020) RNA-Dependent RNA Polymerase as a Target for COVID-19 Drug Discovery. SLAS Discov, 25 (10): 1141-1151. [PMID:32660307]

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