AA sequence: H-Cys1-Lys-Ser-Hyp-Gly-Ser-Ser-Cys8-Ser-Hyp-Thr-Ser-Tyr-Asn-Cys15-Cys16-Arg-Ser-Cys19-Asn-Hyp-Tyr-Thr-Lys-Arg-Cys26-Tyr-NH2
Hyp: hydroxyproline
(Disulfide bonds between Cys1-Cys16, Cys8-Cys19 and Cys15-Cys26)
Length (aa): 27
Formula: C120H182N38O43S6
Molecular Weight: 3036.05 Da
Appearance: White lyophilized solid
Solubility: water and saline buffer
CAS number: [106375-28-4]
Source: Synthetic
Purity rate: > 95 %
ω-Conotoxin-GVIA
Conotoxin GVIA, a selective blocker of Cav2.2 channel
ω-conotoxin-GVIA (omega conotoxin GVIA) is a conotoxin thath has been isolated from the venom of the cone Conus geographus. ω-conotoxin GVIA acts at presynaptic membranes. It binds and blocks specifically voltage-dependent N-type Ca2+channels Cav2.2 channel with an ED50 of 68pM.
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Structure-function relationships of omega-conotoxin GVIA. Synthesis, structure, calcium channel binding, and functional assay of alanine-substituted analogues
The structure-function relationships of the N-type calcium channel blocker, omega-conotoxin GVIA (GVIA), have been elucidated by structural, binding & in vitro & in vivo functional studies of alanine-substituted analogues of the native molecule. Alanine was substituted at all non-bridging positions in the sequence. In most cases the structure of the analogues in aqueous solution was shown to be native-like by 1H NMR spectroscopy. Minor conformational changes observed in some cases were characterized by two-dimensional NMR. Replacement of Lys2 & Tyr13 with Ala caused reductions in potency of more than 2 orders of magnitude in three functional assays (sympathetic nerve stimulation of rat isolated vas deferens, right atrium & mesenteric artery) & a rat brain membrane binding assay. Replacement of several other residues with Ala (particularly Arg17, Tyr22 & Lys24) resulted in significant reductions in potency (<100-fold) in the functional assays, but not the binding assay. The potencies of the analogues were strongly correlated between the different functional assays but not between the functional assays & the binding assay. Thus, the physiologically relevant assays employed in this study have shown that the high affinity of GVIA for the N-type calcium channel is the result of interactions between the channel binding site & the toxin at more sites than the previously identified Lys2 & Tyr13.
Lew, M. J., et al. (1997) Structure-function relationships of omega-conotoxin GVIA. Synthesis, structure, calcium channel binding, and functional assay of alanine-substituted analogues, J Biol Chem. PMID: 9115267
Characteristics of Omega-conotoxin GVIA and MVIIC Binding to Cav 2.1 and Cav 2.2 Channels Captured by Anti-Ca2+ Channel Peptide Antibodies
A New Binding Method (NBM) was used to investigate the characteristics of the specific binding of 125I-omega-conotoxin (omega-CTX) GVIA and 125I-omega-CTX MVIIC to Cav2.1 and Cav2.2 channels captured from chick brain membranes by antibodies against B1Nt (a peptide sequence in Car2.1 & Cav2.2 channels). The results for the NBM were as follows. (1) The ED50 values for specific binding of 125I-omega-CTX GVIA & 125I-omega-CTX MVIIC to Cav2.1 & Cav2.2 channels were about 68 & 60 pM, respectively, & very similar to those (87 & 35 pM, respectively) to crude membranes from chick brain. (2) The specific 125I-omega-CTX GVIA (100 pM) binding was inhibited by omega-CTX GVIA (0.5 nM), dynorphine A (Dyn), gentamicin (Gen), neomycin (Neo) & tobramicin (Tob) (100 microM each), but not by omega-agaconotoxin (Aga) IVA, calciseptine, omega-CTX SVIB, omega-CTX MVIIC (0.5 nM each), PN200-110 (PN), diltiazem (Dil) or verapamil (Ver) (100 microM each). Calmodulin (CaM) inhibited the specific binding in a dose-dependent manner (IC50 value of about 100 microg protein/ml). (3) The specific 125I-omega-CTX MVIIC (60 pM) binding was inhibited by omega-CTX MVIIC, omega-CTX GVIA, omega-CTX SVIB (0.5 nM each), Dyn, Neo & Tob (100 microM, each), but not by omega-Aga IVA, calciseptine (0.5 nM each), PN, Dil, Ver (100 microM each) or 100 microg protein/ml CaM. These results suggested that the characteristics of the specific binding of 125I-omega-CTX GVIA & 125I-omega-CTX MVIIC to Cav2.1 & Cav2.2 channels in the NBM were very similar to those to crude membranes from chick brain, although the IC50 values for CaM & free Ca2+ of CaM were about 33- & 5000-fold higher, respectively, than those for the specific binding of 125I-omega-CTX GVIA & 125I-omega-CTX MVIIC to crude membranes.
N-type calcium channel blockers: novel therapeutics for the treatment of pain
Highly selective Ca(v)2.2 voltage-gated calcium channel (VGCC) inhibitors have emerged as a new class of therapeutics for the treatment of chronic & neuropathic pain. Cone snail venoms provided the first drug in class with FDA approval granted in 2005 to Prialt (omega-conotoxin MVIIA, Elan) for the treatment of neuropathic pain. Since this pioneering work, major efforts underway to develop alternative small molecule inhibitors of Ca(v)2.2 calcium channel have met with varied success. This review focuses on the properties of the Ca(v)2.2 calcium channel in different pain states, the action of omega-conotoxins GVIA, MVIIA & CVID, describing their structure-activity relationships & potential as leads for the design of improved Ca(v)2.2 calcium channel therapeutics, & finally the development of small molecules for the treatment of chronic pain.
Schroeder Cl., et al. (2006) N-type calcium channel blockers: novel therapeutics for the treatment of pain. Med Chem. PMID: 17017994