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CoV Spike glycoprotein

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Target not currently curated in GtoImmuPdb

Target id: 3114

Nomenclature: CoV Spike glycoprotein

Family: Coronavirus (CoV) proteins

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
SARS-CoV-2 1 1273 Orf2 S Spike glycoprotein
SARS-CoV 1 1255 Orf2 S Spike glycoprotein
Previous and Unofficial Names Click here for help
spike protein
Database Links Click here for help
Entrez Gene
RefSeq Protein
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of SARS-CoV-2 spike receptor-binding domain bound with ACE2
PDB Id:  6M0J
Resolution:  2.45Å
Species:  SARS-CoV-2
References:  10
Image of receptor 3D structure from RCSB PDB
Description:  The 2019-nCoV RBD/ACE2-B0AT1 complex
PDB Id:  6M17
Resolution:  2.9Å
Species:  SARS-CoV-2
References:  22
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of SARS-CoV-2 receptor binding domain in complex with human antibody CR3022.
PDB Id:  6W41
Resolution:  3.08Å
Species:  SARS-CoV-2
References:  23
Image of receptor 3D structure from RCSB PDB
Description:  SARS-CoV-2 spike in complex with LCB1 (2RBDs open)
Ligand:  LCB1
Resolution:  2.7Å
Species:  SARS-CoV-2
References:  1

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Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
EK-1 Peptide SARS-CoV Binding - - 20
EK-1-C4 Peptide SARS-CoV-2 Binding - - 19
View species-specific inhibitor tables
Inhibitor Comments
EK-1 and EK-1-C4 are viral fusion inhibitors with broad spectrum activity aginst a range of human coronaviruses [19-20], including escape variants [6].
Key to terms and symbols Click column headers to sort
Antibody Sp. Action Value Parameter Reference
PiN-21 Peptide SARS-CoV-2 Binding >12.0 pKd 21
pKd >12.0 (Kd <1x10-12 M) [21]
Description: Equilibrium dissociation constant for binding to SARS-CoV-2 RBD; determined by SPR assay
regdanvimab Peptide Approved drug SARS-CoV-2 Binding 10.6 pKd 8
pKd 10.6 (Kd 2.7x10-11 M) [8]
Description: Binding affinity to SARS-CoV-2 RBD measured in a surface plasmon resonance assay.
bebtelovimab Peptide SARS-CoV-2 Binding 9.7 – 10.1 pKd 18
pKd 9.7 – 10.1 (Kd 2.2x10-10 – 7.5x10-11 M) [18]
Description: Whole antibody binding affinity to the S protein
CR3022 Peptide SARS-CoV-2 Binding 8.2 pKd 16
pKd 8.2 (Kd 6.3x10-9 M) [16]
mAb 4A8 Peptide SARS-CoV-2 Binding 7.0 pKd 3
pKd 7.0 (Kd 9.27x10-8 M) [3]
Description: Binding affinity to the S1 domain of Spike protein, by bio-layer interferometry.
casirivimab Peptide Approved drug SARS-CoV-2 Binding 10.2 pIC50 5
pIC50 10.2 (IC50 6.9x10-11 M) [5]
Description: IC50 for ability of mAb to compete with spike protein for binding to hACE2.
imdevimab Peptide Approved drug SARS-CoV-2 Binding 9.6 pIC50 5
pIC50 9.6 (IC50 2.3x10-10 M) [5]
Description: IC50 for ability of mAb to compete with spike protein for binding to hACE2.
bamlanivimab Peptide SARS-CoV-2 Binding - -
cilgavimab Peptide Approved drug SARS-CoV-2 Binding - - 24
tixagevimab Peptide Approved drug SARS-CoV-2 Binding - - 24
etesevimab Peptide SARS-CoV-2 Binding - -
sotrovimab Peptide Approved drug SARS-CoV-2 Binding - -
Antibody Comments
CR3022 binds SARS-CoV-1 spike protein with a Kd of 19 nM, using Spike RBD as analyte in a bio-layer interferometry assay [7].

A number of pharmaceutical companies have anti-SARS-CoV-2 spike biologicals in development. Some companies are concentrating on full construct monoclonal antibodies (mAbs), and others are singling out nanobodies derived from immunised camelids. A selection of the mAbs in development are from Regeneron (REGN10933 and REGN10987, casirivimab and imdevimab respectively; administered as a mixture and granted FDA EUA in late 2020), AstraZeneca (AZD1061 and AZD8895, cilgavimab and tixagevimab respectively), EliLilly (LY3832479, etesevimab and LY-CoV555, bamlanivimab; the latter has FDA EUA), and Celltrion (CT-P59, regdanvimab), Nanobodies are being developed by companies including Dioscure Therapeutics (DIOS-202 and DIOS-203), Twist Bioscience, and University of Texas at Austin/NIH/Ghent University.
Adagio Therapeutics have identified an anti-coronavirus mAb (ADG20) with broad-spectrum neutralising activity, including against a number of variants that show varying levels of resistance to existing neutralising antibodies (e.g. P.1 and B.1.351). The epitope for ADG20 resides on the spike protein, at a position that overlaps, but is distinct from the spike's receptor binding domain (RBD: being the target of the majority of existing clinical/lead anti-CoV mAbs). This novel epitope is present in the sarbecoviruses (SARS-CoV and SARS-CoV-2) and some bat coronaviruses, indicating that ADG20 has potential against existing human coronaviruses, and those that may emerge in the future [14]. ADG20 (intramuscular and intravenous doses) will be evaluated in Phase 2/3 clinical trial NCT04805671, in patients with mild-moderate COVID-19 who are at high risk of progressing to severe disease.
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
heparin Small molecule or natural product Approved drug SARS-CoV-2 Binding 10.1 pKd 9
pKd 10.1 (Kd 7.3x10-11 M) [9]
Description: Binding affinity of trimeric SARS-CoV-2 spike protein to immobilized heparin.
heparin Small molecule or natural product Approved drug MERS-CoV Binding 9.0 pKd 9
pKd 9.0 (Kd 1x10-9 M) [9]
LCB1 Peptide SARS-CoV-2 Binding >9.0 pKd 1
pKd >9.0 (Kd <1x10-9 M) [1]
LCB3 Peptide SARS-CoV-2 Binding >9.0 pKd 1
pKd >9.0 (Kd <1x10-9 M) [1]
heparin Small molecule or natural product Approved drug SARS-CoV Binding 6.3 pKd 9
pKd 6.3 (Kd 5x10-7 M) [9]
alunacedase alfa Peptide SARS-CoV-2 Binding - -
ensovibep Peptide SARS-CoV-2 Binding - - 11
SI5α-b Peptide SARS-CoV-2 Binding - - 13
General Comments
Coronavirus (CoV) spike (S) proteins mediate viral entry by attaching to proteins on target host cells. The SARS coronaviruses exploit ACE2 as their primary entry point. Tor2 was isolated and identified as the prototype SARS-CoV during the extensive SARS outbreak in 2002-2003. Its S protein is highly adapted to bind human ACE2.
The SARS CoV S proteins are key to their infection of human cells. S forms trimeric complexes which bind primarily to ACE2 on the surface of host cells to mediate viral entry and to facilitate insertion of its RNA genome into the host cells [22]. Crystal structures of S in closed, open and prefusion configurations have been deposited with the RCSB Protein Data Bank. A structure of spike receptor-binding domain (RBD) bound to ACE2 is represented in PDB accession 6M0J. Experimental evidence suggests that the ACE2 binding domain of SARS-CoV-2 S protein binds to ACE2 more avidly than the homologous domain of SARS-CoV S [17].

The furin cleavage site in SARS-CoV-2's spike protein is necessary for efficient infection, and appears to be required for syncytium formation. Chemical furin inhibitors suppress SARS-CoV-2-induced syncytium and block viral entry and replication [2].

The experimental monoclonal antibody CR3022 was designed to neutralise SARS-CoV [15]. It was developed from an antibody isolated from plasma collected from a convalescent SARS patient. CR3022 was discovered to bind SARS-CoV S protein, including escape mutants. It also binds to the SARS-CoV-2 S protein [23]. X-ray analysis of SARS-CoV-2 spike/CR3022 crystals showed that the antibody targets a highly conserved epitope in S that is distal from the receptor (ACE2)-binding site. The antibody can only gain access to the epitope when at least two RBD on the trimeric S protein are in the "up" conformation. Other anti-spike mAbs were rapidly developed for clinical application. Examples included those from Regeneron (casirivimab + imdevimab) and Eli Lilly (bamlanivimab, etesevimab). The FDA issued Emergency Use Authorisations for the Regeneron cocktail in November 2020, and for single (bamlanivimab) and combined Eli Lilly mAbs (bamlanivimab + etesevimab) in November 2020 and February 2021 respectively. Antibodies that target different components of the virus will potentially be useful as co-agents to anti-spike mAbs for SARS-CoV-2 therapy and/or prophylaxis.

A multi-national group of researchers reported on the design and development of spike-based lipopeptides that can prevent spike fusion with host cells [12]. These peptides are based on the heptad repeat (HR) domain at the C terminus of the S protein, and are termed HRC peptides. The most effective construct ([SARSHRC-PEG4]2-chol) was a dimeric PEG-ylated lipopeptide with a cholesterol tag [4] (bioRxiv preprint). Intranasal administration of this lipopeptide completely blocked direct-contact transmission of SARS-CoV-2 in an experimental animal model, and it blocked fusion of SARS-CoV-2 variants (D614G, B.1.1.7 and B.1.351) as well as SARS-CoV and MERS-CoV in VeroE6 cells. These findings support potential of this approach for pre-exposure and early post-exposure prophylaxis of SARS-CoV-2 transmission.


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4. de Vries RD, Schmitz KS, Bovier FT, Noack D, Haagmans BL, Biswas S, Rockx B, Gellman SH, Alabi CA, de Swart RL et al.. (2020) Intranasal fusion inhibitory lipopeptide prevents direct contact SARS-CoV-2 transmission in ferrets. bioRxiv, Preprint. DOI: 10.1101/2020.11.04.361154 [PMID:33173865]

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9. Kim SY, Jin W, Sood A, Montgomery DW, Grant OC, Fuster MM, Fu L, Dordick JS, Woods RJ, Zhang F et al.. (2020) Characterization of heparin and severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) spike glycoprotein binding interactions. Antiviral Res, 181: 104873. [PMID:32653452]

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