CoV Spike glycoprotein

Target id: 3114

Nomenclature: CoV Spike glycoprotein

Gene and Protein Information
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
spike protein

Database Links
ChEMBL Target	CHEMBL4662936 (SARS-CoV-2), CHEMBL4802007 (SARS-CoV)
Entrez Gene	43740568 (SARS-CoV-2), 1489668 (SARS-CoV)
RefSeq Protein	YP_009825051 (SARS-CoV), YP_009724390 (SARS-CoV-2)
UniProtKB	P0DTC2 (SARS-CoV-2), P59594 (SARS-CoV)

Antibody		Sp.	Action	Value	Parameter	Reference
PiN-21		SARS-CoV-2	Binding	>12.0	pK_d	21
⤷	pK_d >12.0 (K_d <1x10^-12 M) [21] Description: Equilibrium dissociation constant for binding to SARS-CoV-2 RBD; determined by SPR assay
regdanvimab		SARS-CoV-2	Binding	10.6	pK_d	8
⤷	pK_d 10.6 (K_d 2.7x10^-11 M) [8] Description: Binding affinity to SARS-CoV-2 RBD measured in a surface plasmon resonance assay.
masavibart		SARS-CoV-2	Binding	9.9	pK_d	22
⤷	pK_d 9.9 (K_d 1.19x10^-10 M) [22] Description: Binding affinity for monomeric spike RBD protein
bebtelovimab		SARS-CoV-2	Binding	9.7 – 10.1	pK_d	18
⤷	pK_d 9.7 – 10.1 (K_d 2.2x10^-10 – 7.5x10^-11 M) [18] Description: Whole antibody binding affinity to the S protein
CR3022		SARS-CoV-2	Binding	8.2	pK_d	16
⤷	pK_d 8.2 (K_d 6.3x10^-9 M) [16]
mAb 4A8		SARS-CoV-2	Binding	7.0	pK_d	3
⤷	pK_d 7.0 (K_d 9.27x10^-8 M) [3] Description: Binding affinity to the S1 domain of Spike protein, by bio-layer interferometry.
casirivimab		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		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		SARS-CoV-2	Binding	-	-
⤷
cilgavimab		SARS-CoV-2	Binding	-	-	25
⤷	[25]
tixagevimab		SARS-CoV-2	Binding	-	-	25
⤷	[25]
etesevimab		SARS-CoV-2	Binding	-	-
⤷
sotrovimab		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

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Ligand		Sp.	Action	Value	Parameter	Reference
heparin		SARS-CoV-2	Binding	10.1	pK_d	9
⤷	pK_d 10.1 (K_d 7.3x10^-11 M) [9] Description: Binding affinity of trimeric SARS-CoV-2 spike protein to immobilized heparin.
heparin		MERS-CoV	Binding	9.0	pK_d	9
⤷	pK_d 9.0 (K_d 1x10^-9 M) [9]
LCB1		SARS-CoV-2	Binding	>9.0	pK_d	1
⤷	pK_d >9.0 (K_d <1x10^-9 M) [1]
LCB3		SARS-CoV-2	Binding	>9.0	pK_d	1
⤷	pK_d >9.0 (K_d <1x10^-9 M) [1]
heparin		SARS-CoV	Binding	6.3	pK_d	9
⤷	pK_d 6.3 (K_d 5x10^-7 M) [9]
alunacedase alfa		SARS-CoV-2	Binding	-	-
⤷
ensovibep		SARS-CoV-2	Binding	-	-	11
⤷	[11]
SI5α-b		SARS-CoV-2	Binding	-	-	13
⤷	[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 [23]. 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 [24]. 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 ([SARS_HRC-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.

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 [23]. 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 [24]. 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 ([SARS_HRC-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.

References

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