Vc1.1 (P00004) Protein Card

General Information

Name	Vc1.1
Alternative name(s)	ACV1
Organism	synthetic construct
Protein Type	Synthetic
Parent	VcIA
Notes	Satkunanathan et al. (2005) reported that Vc1.1 suppressed mechanical pain responses associated with peripheral neuropathy in rats in vivo and accelerated functional recovery of the injured neurones. Vc1.1 was developped as an analgesic under the name AVC1 by the company Metabolic. Metabolic decided to discontinue its development albeit the Phase 2A trial was completed. It was discovered that Vc1.1 had much lower potency at the human α9α10 nAChR than the rat receptor, which was initially used as an animal model. The rational was that the dose required for human would be much larger than initially thought, making its use in the clinic impractical. Metabolic. Metabolic Discontinues Clinical Trial Programme for Neuropathic Pain Drug, ACV1; Metabolic Pharmaceuticals Ltd.: Melbourne, Australia, 2007. Inhibition of N-type Ca²⁺ channel current through the GABA_B in rat DRG neurons with an IC50 of 1.7nM (Callaghan et al. 2008) and 24.6nM in mouse DRG of an a9 KO mouse (Callaghan et al., 2010). The specific receptor remains unclear. Tabassum et al. (2017) reported that Vc1.1 is a potent inhibitor of hα9α10 and hα3β2 nAChRs, with complete inhibition observed at 10 μM. Castro et al. (2017) highlighted the potential therapeutic value of Vc1.1 in treating chronic visceral pain (CVP). They demonstrated that: (i) The peripheral administration of Vc1.1 in mice strongly inhibited the processing of nociceptive information within colonic sensory pathways; (ii) Both human DRG neurons and mouse colonic DRG neurons expressed the molecular targets of Vc1.1, the GABA_BR and its downstream effector channels Ca_v2.2 and Ca_v2.3; (iii) Vc1.1 inhibited colonic afferents in both the splanchnic and pelvic pathways, and (iv) blocking Ca_v2.2 and Ca_v2.3 caused inhibition comparable with that of Vc1.1 alone. Bony et al. (2022) demonstrated the potential of Vc1.1 as an alternative non-opioid therapeutic for the treatment of chronic pain. The authors showed that (i) 1 µM Vc1.1 potentiated native and recombinant G protein coupled inwardly-rectifying potassium (GIRK)1/2 through activation of G protein-coupled GABA_B receptors; (ii) 1 µM Vc1.1 hyperpolarized the cell, increased action potential firing threshold and reduced mouse dorsal root ganglion (DRG) neuronal excitability similar to 100 µM baclofen.

Classification

Conopeptide class	conotoxin
Gene superfamily
Cysteine framework	I
Pharmacological family	alpha conotoxin

Sequence

GCCSDPRCNYDHPEIC(nh2)

Modified residues

position	symbol	name
17	nh2	C-term amidation

Average Mass

1806.97

Monoisotopic Mass

1805.64

Isoelectric Point

5.63

Extinction Coefficient [280nm]

1490.00

Activity

IC50: Voltage-Gated Calcium Channels

Target	Organism		IC50		n_hill	Agonist	Ref
Ca_v2.2	H. sapiens	(GABABR-coupled CaV2.2)	2.4 nM	[0.8-7]			Cai,F. et al. (2018)

IC50: Nicotinic acetylcholine receptors

Target	Organism		IC50		n_hill	Agonist	Ref
α1β1γδ	R. norvegicus		>30uM			Ach	Clark,R.J. et al. (2006)
α3α5β2	R. norvegicus		7.2uM	+/-0.2	1.3	Ach	Clark,R.J. et al. (2006)
α3α5β4	R. norvegicus		>30uM			Ach	Clark,R.J. et al. (2006)
α3β2	R. norvegicus		>1uM			30-100mM Ach	Safavi-Hemami,H. et al. (2011)
			7.3uM	+/-0.7	1.7	Ach	Clark,R.J. et al. (2006)
			5.5uM			10uM Ach	Halai,R. et al. (2009)
α3β4	R. norvegicus		>3uM			10uM Ach	Halai,R. et al. (2009)
			4.2uM	+/-1.6	1.3	Ach	Clark,R.J. et al. (2006)
α4β2	R. norvegicus		>30uM			Ach	Clark,R.J. et al. (2006)
α4β4	R. norvegicus		>30uM			Ach	Clark,R.J. et al. (2006)
α6/α3β2β3	R. norvegicus		140nM			100uM Ach	Vincler,M. et al. (2006)
α6/α3β4	R. norvegicus		980nM			100uM Ach	Vincler,M. et al. (2006)
α7	H. sapiens		>10 000 nM			Ach (100 uM)	Liang,J. et al. (2020)
	R. norvegicus		7.1uM			10uM Ach	Halai,R. et al. (2009)
			>1uM			30-100mM Ach	Safavi-Hemami,H. et al. (2011)
			>30uM			Ach	Clark,R.J. et al. (2006)
α9α10	H. sapiens	(mutant α9[N154G]α10 α9:α10 subunit ratio of 3:1)	17.02 uM	+/-3.17		Ach (6 uM)	Yu,R. et al. (2018)
		(α9:α10 subunit ratio of 1:3)	1000 nM	+/-100		Ach (6 uM)	Liang,J. et al. (2020)
		(human a9 rat a10)	549nM			10uM Ach	Halai,R. et al. (2009)
		(human a9 rat a10)	975.4nM	+/-314	0.8	50uM Ach	Yu,R. et al. (2013)
		(mutant α9α10[G154N] α9:α10 subunit ratio of 1:3)	0.75 uM	+/-0.05		Ach (6 uM)	Yu,R. et al. (2018)
		(α9:α10 subunit ratio of 3:1)	0.75 uM	+/-0.09		Ach (6 uM)	Yu,R. et al. (2018)
		(α9:α10 subunit ratio of 1:3)	3.57 uM	+/-0.31		Ach (6 uM)	Yu,R. et al. (2018)
		(mutant α9[N154G]α10 α9:α10 subunit ratio of 1:3)	11.25 uM	+/-1.5		Ach (6 uM)	Yu,R. et al. (2018)
	R. norvegicus		28.3 nM	[20.8-38.5]		ACh(6 μM)	Cai,F. et al. (2018)
			109nM			10uM Ach	Halai,R. et al. (2009)
			19nM			10uM Ach	Vincler,M. et al. (2006)
			109nM			30-100 mM Ach	Safavi-Hemami,H. et al. (2011)
			70.0nM	+/-25	1.5	50uM Ach	Yu,R. et al. (2013)
			64.2nM	+/-15	1.1	30uM Ach	Nevin,S.T. et al. (2007)

Percentage inhibition: Nicotinic acetylcholine receptors

Target	Organism	% inhibition		Concentration	Agonist	Ref
α9α10	H. sapiens	42		1 Î¼M	ACh(6 μM)	Chu,X. et al. (2019)
	Unknown	89	+/-5	1uM	30uM Ach	Klimis,H. et al. (2011)
		65	+/-5	100nM	30uM Ach 16	Klimis,H. et al. (2011)

Synthetic variants

Vc1.1 N-term benzoylated	(Bnz)GCCSDPRCNYDHPEIC(nh2)
Vc1.1 [C2(Agl),C8(Agl)]	G(Agl)CSDPR(Agl)NYDHPEIC(nh2)
Vc1.1 [C2(Alk),C8(Alk)]	G(Alk)CSDPR(Alk)NYDHPEIC(nh2)
Vc1.1 [C2(Aly),C8(Aly)]	G(Aly)CSDPR(Aly)NYDHPEIC(nh2)
Vc1.1 [C2H,C8F,insC_GGAAGG] cyclic	GHCSDPRFNYDHPEICGGAAGG
Vc1.1 [C3(Agl),C16(Agl)]	GC(Agl)SDPRCNYDHPEI(Agl)(nh2)
Vc1.1 [D11E,E14A,insC_GGAAGG] cyclic	GCCSDPRCNYEHPAICGGAAGG
Vc1.1 [E14Gla]	GCCSDPRCNYDHP(Gla)IC(nh2)
Vc1.1 [N9W,insC_GGAAGG] cyclic	GCCSDPRCWYDHPEICGGAAGG
Vc1.1 [P6O]	GCCSDORCNYDHPEIC(nh2)
Vc1.1 [insC_GGAAGG]	GCCSDPRCNYDHPEICGGAAGG
Vc1.1 [insC_GGAAGG] cyclic	GCCSDPRCNYDHPEICGGAAGG
Vc1.1 [insN_G,ins_GLPET] cyclic	GGCCSDPRCNYDHPEICGLPET
Vc1.1 dimer	GCCSDPRCNYDHPEICGRRRRGGCCSDPRCNYDHPEIC
Vc1.1[C2H,C8F]	GHCSDPRFNYDHPEIC(nh2)
Vc1.1[D11(Gla)]	GCCSDPRCNY(Gla)HPEIC(nh2)
Vc1.1[D11A]	GCCSDPRCNYAHPEIC(nh2)
Vc1.1[D11E]	GCCSDPRCNYEHPEIC(nh2)
Vc1.1[D11K]	GCCSDPRCNYKHPEIC(nh2)
Vc1.1[D11N]	GCCSDPRCNYNHPEIC(nh2)
Vc1.1[D5A]	GCCSAPRCNYDHPEIC(nh2)
Vc1.1[D5K]	GCCSKPRCNYDHPEIC(nh2)
Vc1.1[E14A]	GCCSDPRCNYDHPAIC(nh2)
Vc1.1[E14D]	GCCSDPRCNYDHPDIC(nh2)
Vc1.1[E14K]	GCCSDPRCNYDHPKIC(nh2)
Vc1.1[G1A]	ACCSDPRCNYDHPEIC(nh2)
Vc1.1[G1D]	DCCSDPRCNYDHPEIC(nh2)
Vc1.1[G1K]	KCCSDPRCNYDHPEIC(nh2)
Vc1.1[H12A]	GCCSDPRCNYDAPEIC(nh2)
Vc1.1[H12D]	GCCSDPRCNYDDPEIC(nh2)
Vc1.1[H12K]	GCCSDPRCNYDKPEIC(nh2)
Vc1.1[I15A]	GCCSDPRCNYDHPEAC(nh2)
Vc1.1[I15D]	GCCSDPRCNYDHPEDC(nh2)
Vc1.1[I15K]	GCCSDPRCNYDHPEKC(nh2)
Vc1.1[N9A]	GCCSDPRCAYDHPEIC(nh2)
Vc1.1[N9D]	GCCSDPRCDYDHPEIC(nh2)
Vc1.1[N9F]	GCCSDPRCFYDHPEIC(nh2)
Vc1.1[N9G]	GCCSDPRCGYDHPEIC(nh2)
Vc1.1[N9I]	GCCSDPRCIYDHPEIC(nh2)
Vc1.1[N9K]	GCCSDPRCKYDHPEIC(nh2)
Vc1.1[N9L]	GCCSDPRCLYDHPEIC(nh2)
Vc1.1[N9R,D11N]	GCCSDPRCRYNHPEIC(nh2)
Vc1.1[N9R,D11R]	GCCSDPRCRYRHPEIC(nh2)
Vc1.1[N9R,D11S]	GCCSDPRCRYSHPEIC(nh2)
Vc1.1[N9R]	GCCSDPRCRYDHPEIC(nh2)
Vc1.1[N9R] N-term benzoylated	(Bnz)GCCSDPRCRYDHPEIC(nh2)
Vc1.1[N9R] acetylated	(Ac)GCCSDPRCRYDHPEIC(nh2)
Vc1.1[N9S,Y10V,D11N,I15L]	GCCSDPRCSVNHPELC(nh2)
Vc1.1[N9W]	GCCSDPRCWYDHPEIC(nh2)
Vc1.1[P13A]	GCCSDPRCNYDHAEIC(nh2)
Vc1.1[P13D]	GCCSDPRCNYDHDEIC(nh2)
Vc1.1[P13K]	GCCSDPRCNYDHKEIC(nh2)
Vc1.1[P6(Hyp)]	GCCSDORCNYDHPEIC(nh2)
Vc1.1[P6A]	GCCSDARCNYDHPEIC(nh2)
Vc1.1[P6D]	GCCSDDRCNYDHPEIC(nh2)
Vc1.1[P6K]	GCCSDKRCNYDHPEIC(nh2)
Vc1.1[R7A]	GCCSDPACNYDHPEIC(nh2)
Vc1.1[R7D]	GCCSDPDCNYDHPEIC(nh2)
Vc1.1[R7K]	GCCSDPKCNYDHPEIC(nh2)
Vc1.1[S4(Dab),N9A]	GCC(Dab)DPRCAYDHPEIC(nh2)
Vc1.1[S4(Dab),N9W]	GCC(Dab)DPRCWYDHPEIC(nh2)
Vc1.1[S4(Dab)]	GCC(Dab)DPRCNYDHPEIC(nh2)
Vc1.1[S4(Dap)]	GCC(Dap)DPRCNYDHPEIC(nh2)
Vc1.1[S4A]	GCCADPRCNYDHPEIC(nh2)
Vc1.1[S4D]	GCCDDPRCNYDHPEIC(nh2)
Vc1.1[S4K,N9A]	GCCKDPRCAYDHPEIC(nh2)
Vc1.1[S4K]	GCCKDPRCNYDHPEIC(nh2)
Vc1.1[S4R]	GCCRDPRCNYDHPEIC(nh2)
Vc1.1[Y10(F(4-Cl))]	GCCSDPRCN(F(4-Cl))DHPEIC(nh2)
Vc1.1[Y10(F(4-F))]	GCCSDPRCN(F(4-F))DHPEIC(nh2)
Vc1.1[Y10A]	GCCSDPRCNADHPEIC(nh2)
Vc1.1[Y10D]	GCCSDPRCNDDHPEIC(nh2)
Vc1.1[Y10F]	GCCSDPRCNFDHPEIC(nh2)
Vc1.1[Y10K]	GCCSDPRCNKDHPEIC(nh2)
Vc1.1[del 9-16, C3S]	GCSSDPRC(nh2)
Vc1.1[del1G,N9R]	CCSDPRCRYDHPEIC(nh2)
Vc1.1[insC_G(Nmv)G(Nmv)GV] cyclic	GCCSDPRCNYDHPEICG(Nmv)G(Nmv)GV
Vc1.1[insC_GE(Nmg)E(Nmg)E] cyclic	GCCSDPRCNYDHPEICGE(Nmg)E(Nmg)E
Vc1.1[insC_GK(Nmg)KGK] cyclic	GCCSDPRCNYDHPEICGK(Nmg)KGK
hVc1.1	GHCSDPRFNYDHPEICGGAAGG

References

Clark,R.J., Fischer,H., Nevin,S.T., Adams,D.J. and Craik,D.J. (2006) The synthesis, structural characterization, and receptor specificity of the alpha-conotoxin Vc1.1 J. Biol. Chem. 281:23254-23263

Sandall,D.W., Satkunanathan,N., Keays,D.A., Polidano,M.A., Liping,X., Pham,V., Down,J.G., Khalil,Z., Livett,B.G. and Gayler,K.R. (2003) A novel alpha-conotoxin identified by gene sequencing is active in suppressing the vascular response to selective stimulation of sensory nerves in vivo Biochemistry 42:6904-6911

Satkunanathan,N., Livett,B., Gayler,K., Sandall,D., Down,J. and Khalil,Z. (2005) Alpha-conotoxin Vc1.1 alleviates neuropathic pain and accelerates functional recovery of injured neurones Brain Res. 1059:149-158

Safavi-Hemami,H., Siero,W.A., Kuang,Z., Williamson,N.A., Karas,J.A., Page,L.R., MacMillan,D., Callaghan,B., Kompella,S.N., Adams,D.J., Norton,R.S., and Purcell,A.W. (2011) Embryonic toxin expression in the cone snail Conus victoriae: primed to kill or divergent function? J. Biol. Chem. 286:22546-22557

Halai,R., Clark,R.J., Nevin,S.T., Jensen,J.E., Adams,D.J. and Craik,D.J. (2009) Scanning mutagenesis of alpha-conotoxin Vc1.1 reveals residues crucial for activity at the alpha9alpha10 nicotinic acetylcholine receptor. J. Biol. Chem.

Vincler,M., Wittenauer,S., Parker,R., Ellison,M., Olivera,B.M. and McIntosh,J.M. (2006) Molecular mechanism for analgesia involving specific antagonism of alpha9alpha10 nicotinic acetylcholine receptors. Proc. Natl. Acad. Sci. U.S.A. 103:17880-17884

Cuny,H., Kompella,S.N., Tae,H.S., Yu,R. and Adams,D.J. (2016) Key Structural Determinants in the Agonist Binding Loops of Human β2 and β4 Nicotinic Acetylcholine Receptor Subunits Contribute to α3β4 Subtype Selectivity of α-Conotoxins. J. Biol. Chem. 291:23779-23792

Klimis,H., Adams,D.J., Callaghan,B., Nevin,S., Alewood,P.F., Vaughan,C.W., Mozar,C.A. and Christie,M.J. (2011) A novel mechanism of inhibition of high-voltage activated calcium channels by α-conotoxins contributes to relief of nerve injury-induced neuropathic pain. Pain 152:259-266

Nevin,S.T., Clark,R.J., Klimis,H., Christie,M.J., Craik,D.J. and Adams,D.J. (2007) Are alpha9alpha10 nicotinic acetylcholine receptors a pain target for alpha-conotoxins? Mol. Pharmacol. 72:1406-1410

Callaghan,B., Haythornthwaite,A., Berecki,G., Clark,R.J., Craik,D.J. and Adams,D.J. (2008) Analgesic alpha-conotoxins Vc1.1 and Rg1A inhibit N-type calcium channels in rat sensory neurons via GABAB receptor activation. J. Neurosci. 28:10943-10951

Yu,R., Kompella,S.N., Adams,D.J., Craik,D.J. and Kaas,Q. (2013) Determination of the α-Conotoxin Vc1.1 Binding Site on the α9α10 Nicotinic Acetylcholine Receptor. J. Med. Chem.

Tabassum, N., Tae, H.S., Jia, X., Kaas, Q., Jiang, T., Adams, D.J. and Yu, R. (2017) Role of CysI-CysIII Disulfide Bond on the Structure and Activity of α-Conotoxins at Human Neuronal Nicotinic Acetylcholine Receptors ACS omega 2:4621-4631

Liang,J., Tae,H.S., Xu,X., Jiang,T., Adams,D.J. and Yu,R (2020) Dimerization of α-Conotoxins as a Strategy to Enhance the Inhibition of the Human α7 and α9α10 Nicotinic Acetylcholine Receptors J. Med. Chem 63:2974-2985

Chu,X., Tae,H.S., Xu,Q., Jiang,T., Adams,D.J. and Yu,R (2019) α-Conotoxin Vc1.1 Structure-Activity Relationship at the Human α9α10 Nicotinic Acetylcholine Receptor Investigated by Minimal Side Chain Replacement ACS Chem Neurosci 10:4328-4336

Yu,R., Tae,H.S., Tabassum,N., Shi,J., Jiang,T. and Adams,D.J. (2018) Molecular Determinants Conferring the Stoichiometric-Dependent Activity of α-Conotoxins at the Human α9α10 Nicotinic Acetylcholine Receptor Subtype J. Med. Chem. 61:4628-4634

Cai,F., Xu,N., Liu,Z., Ding,R., Yu,S., Dong,M., Wang,S., Shen,J., Tae,H.S., Adams,D.J., Zhang,X. and Dai,Q. (2018) Targeting of N-Type Calcium Channels via GABAB-Receptor Activation by α-Conotoxin Vc1.1 Variants Displaying Improved Analgesic Activity J. Med. Chem. 61:10198-10205

Callaghan,B. and Adams,D.J. (2010) Analgesic α-conotoxins Vc1.1 and RgIA inhibit N-type calcium channels in sensory neurons of α9 nicotinic receptor knockout mice. Channels (Austin) 4:51-54

Castro,J., Harrington,A.M., Garcia-Caraballo,S., Maddern,J., Grundy,L., Zhang,J., Page,G., Miller,P.E., Craik,D.J., Adams,D.J. and Brierley,S.M. (2017) α-Conotoxin Vc1.1 inhibits human dorsal root ganglion neuroexcitability and mouse colonic nociception via GABA_B receptors. 66:1083-1094

Belgi,A., Burnley,J.V., MacRaild,C.A., Chhabra,S., Elnahriry,K.A., Robinson,S.D., Gooding,S.G., Tae,H.S., Bartels,P., Sadeghi,M., Zhao,F.Y., Wei,H., Spanswick,D., Adams,D.J., Norton,R.S. and Robinson,A.J. (2021) Alkyne-Bridged α-Conotoxin Vc1.1 Potently Reverses Mechanical Allodynia in Neuropathic Pain Models. J Med Chem 64:3222-3233

Bony,A.R., McArthur,J.R., Finol-Urdaneta,R.K., and Adams,D.J. (2022) Analgesic α-conotoxins modulate native and recombinant GIRK1/2 channels via activation of GABAB receptors and reduce neuroexcitability. Br J Pharmacol 179:179-198

Internal links

Nucleic acids
Structure	SOLUTION STRUCTURE OF ALPHA-CONOTOXIN VC1.1

External links

Ncbi

2H8S_A

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