Coronavirus (CoV) proteins | Other protein targets | IUPHAR/BPS Guide to IMMUNOPHARMACOLOGY

Coronavirus (CoV) proteins C

Overview

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Coronaviruses are large, often spherical, enveloped, single-stranded positive-sense RNA viruses, ranging in size from 80-220 nm. Their genomes and protein structures are highly conserved. Three coronaviruses have emerged over the last 20 years as serious human pathogens: SARS-CoV was identified as the causative agent in an outbreak in 2002-2003, Middle East respiratory syndrome (MERS) CoV emerged in 2012 and the novel coronavirus SARS-CoV-2 emerged in 2019-2020. SARS-CoV-2 is the virus responsible for the infectious disease termed COVID-19 (WHO Technical Guidance 2020).

Targets

Targets of relevance to immunopharmacology are highlighted in blue

CoV Envelope protein Show summary »« Hide summary More detailed page go icon to follow link

Target Id	3116
Nomenclature	CoV Envelope protein
Previous and unofficial names	envelope small membrane protein \| orf4
UniProtKB AC	P0DTC4 (SARS-CoV-2), P59637 (SARS-CoV)
Comment	By similarity to other coronavirus E proteins, SARS-CoV-2 E is predicted to constitute a single transmembrane (potentially homopentameric) ion channel with selectivity for monovalent cations over monovalent anions [16,24,28,31].

CoV 3C-like (main) protease C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

3111

Nomenclature

CoV 3C-like (main) protease

Previous and unofficial names

UniProtKB AC

P0C6U8 (SARS-CoV)

EC number (SARS-CoV-2)

3.4.22.69

Inhibitors

nirmatrelvir pK_i 9.6 [15] - SARS-CoV-2

bofutrelvir pIC₅₀ 7.3 [2] - SARS-CoV-2

Comment

The Mpro enzyme (also known as nsp5 or 3CL protease) cleaves the two polyproteins encoded by the SARS-CoV-2 genome (pp1a and pp1ab) into a range of non-structural proteins (nsp1-11 from pp1a; nsp1-16 from pp1ab). As these component proteins play crucial roles in viral replication, Mpro is considered to be a strong molecular target for drug development. Small molecule Mpro inhibitors would be predicted to reduce viral replication [9,13,19].

CoV Membrane glycoprotein Show summary »« Hide summary More detailed page go icon to follow link

Target Id	3117
Nomenclature	CoV Membrane glycoprotein
Previous and unofficial names	membrane protein
UniProtKB AC	P0DTC5 (SARS-CoV-2), P59596 (SARS-CoV)
Comment	The membrane glycoprotein (M) is usually regarded as the most abundant protein in the coronavirus envelope. By similarity with other coronavirus M proteins it is predicted to be essential for initiating assembly of the viral envelope components [20,32].

CoV Non-structural protein 6 Show summary »« Hide summary More detailed page go icon to follow link

Target Id	3118
Nomenclature	CoV Non-structural protein 6
Previous and unofficial names	nsp6
UniProtKB AC	P0DTC6 (SARS-CoV-2), P59634 (SARS-CoV)
Comment	Coronavirus nsp6 proteins limit autophagosome expansion [1]. This mechanism may favour coronavirus infection by damaging autophagosome-mediated delivery of viral components to lysosomes for degradation.

CoV Non-structural protein 7b Show summary »« Hide summary More detailed page go icon to follow link

Target Id	3123
Nomenclature	CoV Non-structural protein 7b
Previous and unofficial names	Accessory protein 7b \| nsp7b
UniProtKB AC	P0DTD8 (SARS-CoV-2), Q7TFA1 (SARS-CoV)
Comment	Protein 7b is a coronavirus accessory protein. Experimental evidence suggests that SARS-CoV 7b has some attenuating function [18]. By homology, SARS-CoV-2 7b is likely to have a similar function.

CoV Non-structural protein 8 Show summary »« Hide summary More detailed page go icon to follow link

Target Id	3120
Nomenclature	CoV Non-structural protein 8
Previous and unofficial names	nsp8
UniProtKB AC	P0DTC8 (SARS-CoV-2)
Comment	Coronavirus nsp8 proteins form a hexadecameric complex with nsp7 proteins (8 subunits of each) [10,26]. This complex may participate in viral replication by acting as a primase for de novo initiation of RNA synthesis.

CoV Non-structural protein 13 Show summary »« Hide summary More detailed page go icon to follow link

Target Id	3261
Nomenclature	CoV Non-structural protein 13
UniProtKB AC	P0DTD1 (SARS-CoV-2)
Comment	Nsp13 is a helicase that is encoded by coronavirus (CoV) RNAs. The SARS-CoV-2 nsp13 is 600 aa long. Small molecule nsp13 inhibitors are proposed as novel CoV antivirals.

CoV Non-structural protein 14 Show summary »« Hide summary More detailed page go icon to follow link

Target Id	3198
Nomenclature	CoV Non-structural protein 14
Previous and unofficial names	(N7-guanine)-methyltransferase \| N7-MTase
UniProtKB AC	P0DTD8 (SARS-CoV-2), P59634 (SARS-CoV)

CoV Non-structural protein 15 C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

3206

Nomenclature

CoV Non-structural protein 15

Previous and unofficial names

NendoU | NSP15

UniProtKB AC

P0DTD1 (SARS-CoV-2), P0C6X7 (SARS-CoV)

Inhibitors

tipiracil [12] - SARS-CoV-2

Comment

Nsp15 (NendoU) is a uridylate-specific endoribonuclease that is essential during the coronavirus lifecycle. The search for inhibitors of SARS-CoV-2 nsp15 that may have antiviral action is ongoing. Two allosteric inhibitors have been reported, FUZS-5 (12200) and LIZA-7 (12199). The docking positions of these compounds within nsp15 have been determined by X-ray crystallography [5].

CoV Nucleoprotein Show summary »« Hide summary More detailed page go icon to follow link

Target Id	3121
Nomenclature	CoV Nucleoprotein
Previous and unofficial names	nucleocapsid phosphoprotein
UniProtKB AC	P0DTC9 (SARS-CoV-2), P59595 (SARS-CoV)
Comment	The coronavirus nucleocapsid phosphoprotein (N, or nucleoprotein) is highly basic and binds the viral RNA as a dimeric entity [3] into nucleocapsids which protect the viral genome, while also providing access for replication when required.

CoV Papain-like protease C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

3132

Nomenclature

CoV Papain-like protease

Previous and unofficial names

non-structural protein 3 | NS3 | nsp3 | PL-PRO

UniProtKB AC

P0DTC1 (SARS-CoV-2)

EC number (SARS-CoV-2)

3.4.22.46

Inhibitors

XR8-23 pIC₅₀ 6.4 [21] - SARS-CoV-2

GRL-0617 pIC₅₀ 5.6 – 5.6 [4,14] - SARS-CoV-2

Comment

PL-pro is a domain within coronavirus Nsp3. Its proteolytic activity cleaves three sites in the viral replicase polyprotein (recognition consensus sequence LXGG↓XX) to release the three non-structural proteins Nsp1, Nsp2, and Nsp3 [8]. It has additional non-proteolytic functions as part of the multicomponent replicase-transcriptase complex [23].

CoV Protein 3a Show summary »« Hide summary More detailed page go icon to follow link

Target Id	3115
Nomenclature	CoV Protein 3a
Previous and unofficial names	orf3a
UniProtKB AC	P0DTC3 (SARS-CoV-2), P59632 (SARS-CoV)
Comment	Protein 3a is a transmembrane pore-forming viral protein (viroporin) with potassium ion channel activity.

CoV Protein 7a Show summary »« Hide summary More detailed page go icon to follow link

Target Id	3119
Nomenclature	CoV Protein 7a
Previous and unofficial names	orf7a
UniProtKB AC	P0DTC7 (SARS-CoV-2), P59635 (SARS-CoV)
Comment	The main function of the SARS-CoV protein 7a appears to be disruption of host the cell cycle and induction of caspase-dependent apoptosis [25]. By homology SARS-CoV-2 protein 7a is likely to produce the same effect.

CoV Protein 9b Show summary »« Hide summary More detailed page go icon to follow link

Target Id	3122
Nomenclature	CoV Protein 9b
Previous and unofficial names	orf9b \| Accessory protein 9b \| ORF-9b
UniProtKB AC	P0DTD2 (SARS-CoV-2), P59636 (SARS-CoV)
Comment	SARS-CoV protein 9b is a virion-associated accessory protein [30] that acts to block the host's ability to mount an antiviral IFN-induced innate immune response [22]. By homology, 9b from SARS-CoV-2 would be predicted to exhibit a similar function.

CoV Replicase polyprotein 1a Show summary »« Hide summary More detailed page go icon to follow link

Target Id	3124
Nomenclature	CoV Replicase polyprotein 1a
UniProtKB AC	P0DTC1 (SARS-CoV-2), P0C6U8 (SARS-CoV)
Comment	The replicase polyprotein 1a (pp1a) encodes a set of 11 smaller proteins, including two proteases that are responsible for cleaving the polyprotein chain into its component parts. The components are non-structural and are involved in the transcription and replication of viral proteins and RNA.

CoV Replicase polyprotein 1ab Show summary »« Hide summary More detailed page go icon to follow link

Target Id	3125
Nomenclature	CoV Replicase polyprotein 1ab
UniProtKB AC	P0DTD1 (SARS-CoV-2), P0C6X7 (SARS-CoV)
Comment	The replicase polyprotein 1ab (pp1ab) encodes a set of 15 smaller proteins (5 more than pp1a), including two proteases that are responsible for cleaving the polyprotein chain into its component parts. The components are non-structural and are involved in the transcription and replication of viral proteins and RNA.

CoV RNA-dependent RNA polymerase C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

3139

Nomenclature

CoV RNA-dependent RNA polymerase

Previous and unofficial names

non-structural protein 12 | nsp12

UniProtKB AC

P0DTD1 (SARS-CoV-2), P0C6X7 (SARS-CoV)

Inhibitors

remdesivir [6] - SARS-CoV-2

remdesivir [6] - SARS-CoV

Comment

The conservation of RdRP catalytic domain between different RNA viruses endows inhibitors that were designed against other viral pathogens with activity against the SARS coronaviruses. Viral RdRP is the molecular target of nucleotide-based broad-spectrum antiviral compounds like remdesivir, tenofovir and ribavirin [6,27,33].

CoV Spike glycoprotein C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

3114

Nomenclature

CoV Spike glycoprotein

Previous and unofficial names

spike protein

UniProtKB AC

P0DTC2 (SARS-CoV-2), P59594 (SARS-CoV)

Inhibitors

EK-1-C4 (Binding) [29] - SARS-CoV-2

Antibodies

regdanvimab (Binding) pK_d 10.6 [11] - SARS-CoV-2

casirivimab (Binding) pIC₅₀ 10.2 [7] - SARS-CoV-2

Comment

The spike protein on the surface of CoV particles is central for viral infection of host cells (by binding to ACE2). It is the molecular target of a wide range of clinically approved monoclonal antibodies that reduce infection. At any point in time, the efficacy of these therapeutics is heavily dependent upon spike mutations in the circulating CoV variants. Spike is also the antigen that's exploited for raising anti-CoV immunity by inoculation with either mRNA and/or adenovirus vaccines that induce spike protein expression.

Comments

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References

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2. Dai W, Zhang B, Jiang XM, Su H, Li J, Zhao Y, Xie X, Jin Z, Peng J, Liu F et al.. (2020) Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease. Science, 368 (6497): 1331-1335. [PMID:32321856]

3. Fan H, Ooi A, Tan YW, Wang S, Fang S, Liu DX, Lescar J. (2005) The nucleocapsid protein of coronavirus infectious bronchitis virus: crystal structure of its N-terminal domain and multimerization properties. Structure, 13 (12): 1859-68. [PMID:16338414]

4. Freitas BT, Durie IA, Murray J, Longo JE, Miller HC, Crich D, Hogan RJ, Tripp RA, Pegan SD. (2020) Characterization and Noncovalent Inhibition of the Deubiquitinase and deISGylase Activity of SARS-CoV-2 Papain-Like Protease. ACS Infect Dis, 6 (8): 2099-2109. [PMID:32428392]

5. Godoy AS, Nakamura AM, Douangamath A, Song Y, Noske GD, Gawriljuk VO, Fernandes RS, Pereira HDM, Oliveira KIZ, Fearon D et al.. (2023) Allosteric regulation and crystallographic fragment screening of SARS-CoV-2 NSP15 endoribonuclease. Nucleic Acids Res, 51 (10): 5255-5270. DOI: 10.1101/2022.09.26.509485 [PMID:37115000]

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12. Kim Y, Wower J, Maltseva N, Chang C, Jedrzejczak R, Wilamowski M, Kang S, Nicolaescu V, Randall G, Michalska K et al.. (2021) Tipiracil binds to uridine site and inhibits Nsp15 endoribonuclease NendoU from SARS-CoV-2. Commun Biol, 4 (1): 193. [PMID:33564093]

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14. Osipiuk J, Azizi SA, Dvorkin S, Endres M, Jedrzejczak R, Jones KA, Kang S, Kathayat RS, Kim Y, Lisnyak VG et al.. (2021) Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors. Nat Commun, 12 (1): 743. [PMID:33531496]

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18. Pfefferle S, Krähling V, Ditt V, Grywna K, Mühlberger E, Drosten C. (2009) Reverse genetic characterization of the natural genomic deletion in SARS-Coronavirus strain Frankfurt-1 open reading frame 7b reveals an attenuating function of the 7b protein in-vitro and in-vivo. Virol J, 6: 131. [PMID:19698190]

19. Pillaiyar T, Manickam M, Namasivayam V, Hayashi Y, Jung SH. (2016) An Overview of Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy. J Med Chem, 59 (14): 6595-628. [PMID:26878082]

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Alexander SPH, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Buneman OP, Faccenda E, Harding SD, Spedding M, Cidlowski JA, Fabbro D, Davenport AP, Striessnig J, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Introduction and Other Protein Targets. Br J Pharmacol. 180 Suppl 2:S1-22.