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 GABAB 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:

  • The peripheral administration of Vc1.1 in mice strongly inhibits the processing of nociceptive information within colonic sensory pathways.
  • Both human DRG neurons and mouse colonic DRG neurons express the molecular targets of Vc1.1, the GABABR and its downstream effector channels Cav2.2 and Cav2.3.
  • Vc1.1 inhibits colonic afferents in both the splanchnic and pelvic pathways, and
  • blocking Cav2.2 and Cav2.3 causes inhibition comparable with that of Vc1.1 alone.

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

    Sequence
    GCCSDPRCNYDHPEIC(nh2)
    Modified residues
    positionsymbolname
    17nh2C-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

    TargetOrganismIC50nhillAgonistRef
    Cav2.2H. sapiens(GABABR-coupled CaV2.2)2.4 nM[0.8-7]Cai,F. et al. (2018)

    IC50: Nicotinic acetylcholine receptors

    TargetOrganismIC50nhillAgonistRef
    α1β1γδR. norvegicus>30uMAchClark,R.J. et al. (2006)
    α3α5β2R. norvegicus7.2uM+/-0.21.3AchClark,R.J. et al. (2006)
    α3α5β4R. norvegicus>30uMAchClark,R.J. et al. (2006)
    α3β2R. norvegicus5.5uM10uM AchHalai,R. et al. (2009)
    >1uM30-100mM AchSafavi-Hemami,H. et al. (2011)
    7.3uM+/-0.71.7AchClark,R.J. et al. (2006)
    α3β4R. norvegicus>3uM10uM AchHalai,R. et al. (2009)
    4.2uM+/-1.61.3AchClark,R.J. et al. (2006)
    α4β2R. norvegicus>30uMAchClark,R.J. et al. (2006)
    α4β4R. norvegicus>30uMAchClark,R.J. et al. (2006)
    α6/α3β2β3R. norvegicus140nM100uM AchVincler,M. et al. (2006)
    α6/α3β4R. norvegicus980nM100uM AchVincler,M. et al. (2006)
    α7H. sapiens>10 000 nMAch (100 uM)Liang,J. et al. (2020)
    R. norvegicus7.1uM10uM AchHalai,R. et al. (2009)
    >1uM30-100mM AchSafavi-Hemami,H. et al. (2011)
    >30uMAchClark,R.J. et al. (2006)
    α9α10H. sapiens(α9:α10 subunit ratio of 3:1)0.75 uM+/-0.09Ach (6 uM)Yu,R. et al. (2018)
    (human a9 rat a10)975.4nM+/-3140.850uM AchYu,R. et al. (2013)
    (mutant α9[N154G]α10 α9:α10 subunit ratio of 3:1)17.02 uM+/-3.17Ach (6 uM)Yu,R. et al. (2018)
    (human a9 rat a10)549nM10uM AchHalai,R. et al. (2009)
    (α9:α10 subunit ratio of 1:3)3.57 uM+/-0.31Ach (6 uM)Yu,R. et al. (2018)
    (α9:α10 subunit ratio of 1:3)1000 nM+/-100Ach (6 uM)Liang,J. et al. (2020)
    (mutant α9[N154G]α10 α9:α10 subunit ratio of 1:3)11.25 uM+/-1.5Ach (6 uM)Yu,R. et al. (2018)
    (mutant α9α10[G154N] α9:α10 subunit ratio of 1:3)0.75 uM+/-0.05Ach (6 uM)Yu,R. et al. (2018)
    R. norvegicus109nM30-100 mM AchSafavi-Hemami,H. et al. (2011)
    109nM10uM AchHalai,R. et al. (2009)
    70.0nM+/-251.550uM AchYu,R. et al. (2013)
    19nM10uM AchVincler,M. et al. (2006)
    64.2nM+/-151.130uM AchNevin,S.T. et al. (2007)
    28.3 nM[20.8-38.5]ACh(6 μM)Cai,F. et al. (2018)

    Percentage inhibition: Nicotinic acetylcholine receptors

    TargetOrganism% inhibitionConcentrationAgonistRef
    α9α10H. sapiens42%1 μMACh(6 μM)Chu,X. et al. (2019)
    Unknown65+/-5100nM30uM Ach 16 Klimis,H. et al. (2011)
    89+/-51uM30uM AchKlimis,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 [C2H,C8F,insC_GGAAGG] cyclicGHCSDPRFNYDHPEICGGAAGG
    Vc1.1 [C3(Agl),C16(Agl)]GC(Agl)SDPRCNYDHPEI(Agl)(nh2)
    Vc1.1 [D11E,E14A,insC_GGAAGG] cyclicGCCSDPRCNYEHPAICGGAAGG
    Vc1.1 [E14Gla]GCCSDPRCNYDHP(Gla)IC(nh2)
    Vc1.1 [N9W,insC_GGAAGG] cyclicGCCSDPRCWYDHPEICGGAAGG
    Vc1.1 [P6O]GCCSDORCNYDHPEIC(nh2)
    Vc1.1 [insC_GGAAGG]GCCSDPRCNYDHPEICGGAAGG
    Vc1.1 [insC_GGAAGG] cyclicGCCSDPRCNYDHPEICGGAAGG
    Vc1.1 [insN_G,ins_GLPET] cyclicGGCCSDPRCNYDHPEICGLPET
    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] cyclicGCCSDPRCNYDHPEICG(Nmv)G(Nmv)GV
    Vc1.1[insC_GE(Nmg)E(Nmg)E] cyclicGCCSDPRCNYDHPEICGE(Nmg)E(Nmg)E
    Vc1.1[insC_GK(Nmg)KGK] cyclicGCCSDPRCNYDHPEICGK(Nmg)KGK
    hVc1.1GHCSDPRFNYDHPEICGGAAGG

    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 GABAB receptors. 66:1083-1094

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

    External links
    Ncbi 2H8S_A

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