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SNX 482

* Please kindly note that our products are not to be used for therapeutic purposes and cannot be sold to patients.

SNX-482 has been isolated from the venom of the Spider Hysterocrates gigas (African tarantula). SNX-482 modulates the R-type current associated with the class α1E calcium channel (Cav2.3 from the CACNA1E gene).

Category

Peptide Inhibitors

Catalog number

BAT-010350

CAS number

203460-30-4

Molecular Formula

C192H274N52O60S7

Molecular Weight

4495.01

Specification
Reference Reading

IUPAC Name

(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(1R,7S,10S,13S,19R,24R,27S,30S,33S,36S,45R,48S,51S,54S,57S,60S,63R,68R,71S,74S,77S,80S,83S,86S)-24-[[2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[(2-aminoacetyl)amino]-3-methylbutanoyl]amino]-3-carboxypropanoyl]amino]hexanoyl]amino]propanoyl]amino]acetyl]amino]-54-(2-amino-2-oxoethyl)-36,77-dibenzyl-10,27-bis(3-carbamimidamidopropyl)-57,60-bis(carboxymethyl)-48,74,83-tris(hydroxymethyl)-30,71-bis[(4-hydroxyphenyl)methyl]-86-(1H-imidazol-4-ylmethyl)-7,80-bis(2-methylpropyl)-33-(2-methylsulfanylethyl)-3,6,9,12,18,25,28,31,34,37,40,43,46,49,52,55,58,61,70,73,76,79,82,85,88,93-hexacosaoxo-51-propan-2-yl-21,22,65,66,90,91-hexathia-2,5,8,11,17,26,29,32,35,38,41,44,47,50,53,56,59,62,69,72,75,78,81,84,87,94-hexacosazatetracyclo[43.43.4.219,63.013,17]tetranonacontane-68-carbonyl]amino]propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-carboxypropanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-phenylpropanoyl]amino]-3-hydroxypropanoyl]amino]butanedioic acid

Synonyms

SNX-482; SNX482; H-Gly-Val-Asp-Lys-Ala-Gly-Cys(1)-Arg-Tyr-Met-Phe-Gly-Gly-Cys(2)-Ser-Val-Asn-Asp-Asp-Cys(3)-Cys(1)-Pro-Arg-Leu-Gly-Cys(2)-His-Ser-Leu-Phe-Ser-Tyr-Cys(3)-Ala-Trp-Asp-Leu-Thr-Phe-Ser-Asp-OH; glycyl-L-valyl-L-alpha-aspartyl-L-lysyl-L-alanyl-glycyl-L-cysteinyl-L-arginyl-L-tyrosyl-L-methionyl-L-phenylalanyl-glycyl-glycyl-L-cysteinyl-L-seryl-L-valyl-L-asparagyl-L-alpha-aspartyl-L-alpha-aspartyl-L-cysteinyl-L-cysteinyl-L-prolyl-L-arginyl-L-leucyl-glycyl-L-cysteinyl-L-histidyl-L-seryl-L-leucyl-L-phenylalanyl-L-seryl-L-tyrosyl-L-cysteinyl-L-alanyl-L-tryptophyl-L-alpha-aspartyl-L-leucyl-L-threonyl-L-phenylalanyl-L-seryl-L-aspartic acid (7->21),(14->26),(20->33)-tris(disulfide)

Appearance

White lyophilized solid

Purity

>98%

Sequence

GVDKAGCRYMFGGCSVNDDCCPRLGCHSLFSYCAWDLTFSD (Disulfide bridge: Cys7 and Cys21, Cys14 and Cys26, Cys20 and Cys33)

Storage

Store at -20°C

Solubility

Soluble in water, aqueous buffer

InChI

InChI=1S/C192H274N52O60S7/c1-91(2)57-114-157(270)207-79-146(257)213-135-85-306-307-86-136-183(296)237-133(83-248)179(292)242-153(95(9)10)187(300)231-124(67-141(195)252)170(283)228-126(69-148(260)261)173(286)229-127(70-149(262)263)174(287)239-138(184(297)240-139(189(302)244-55-30-42-140(244)185(298)217-112(161(274)219-114)41-29-54-202-192(198)199)89-311-308-84-134(212-145(256)78-205-155(268)96(11)209-159(272)110(39-26-27-52-193)214-171(284)128(71-150(264)265)232-186(299)152(94(7)8)241-142(253)73-194)181(294)215-111(40-28-53-201-191(196)197)160(273)223-119(63-102-43-47-106(250)48-44-102)164(277)216-113(51-56-305-14)162(275)222-117(60-99-31-18-15-19-32-99)158(271)206-76-143(254)204-77-144(255)211-136)88-310-309-87-137(238-167(280)120(64-103-45-49-107(251)50-46-103)225-177(290)131(81-246)234-165(278)118(61-100-33-20-16-21-34-100)224-163(276)115(58-92(3)4)221-176(289)130(80-245)236-169(282)123(226-182(135)295)66-105-75-200-90-208-105)180(293)210-97(12)156(269)218-122(65-104-74-203-109-38-25-24-37-108(104)109)168(281)227-125(68-147(258)259)172(285)220-116(59-93(5)6)175(288)243-154(98(13)249)188(301)230-121(62-101-35-22-17-23-36-101)166(279)235-132(82-247)178(291)233-129(190(303)304)72-151(266)267/h15-25,31-38,43-50,74-75,90-98,110-140,152-154,203,245-251H,26-30,39-42,51-73,76-89,193-194H2,1-14H3,(H2,195,252)(H,200,208)(H,204,254)(H,205,268)(H,206,271)(H,207,270)(H,209,272)(H,210,293)(H,211,255)(H,212,256)(H,213,257)(H,214,284)(H,215,294)(H,216,277)(H,217,298)(H,218,269)(H,219,274)(H,220,285)(H,221,289)(H,222,275)(H,223,273)(H,224,276)(H,225,290)(H,226,295)(H,227,281)(H,228,283)(H,229,286)(H,230,301)(H,231,300)(H,232,299)(H,233,291)(H,234,278)(H,235,279)(H,236,282)(H,237,296)(H,238,280)(H,239,287)(H,240,297)(H,241,253)(H,242,292)(H,243,288)(H,258,259)(H,260,261)(H,262,263)(H,264,265)(H,266,267)(H,303,304)(H4,196,197,201)(H4,198,199,202)/t96-,97-,98+,110-,111-,112-,113-,114-,115-,116-,117-,118-,119-,120-,121-,122-,123-,124-,125-,126-,127-,128-,129-,130-,131-,132-,133-,134-,135-,136-,137-,138-,139-,140-,152-,153-,154-/m0/s1

InChI Key

NSUPRLHDCFNOKD-CICZDBDCSA-N

Canonical SMILES

CC(C)CC1C(=O)NCC(=O)NC2CSSCC3C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(CSSCC(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC2=O)CC4=CNC=N4)CO)CC(C)C)CC5=CC=CC=C5)CO)CC6=CC=C(C=C6)O)C(=O)NC(C)C(=O)NC(CC7=CNC8=CC=CC=C87)C(=O)NC(CC(=O)O)C(=O)NC(CC(C)C)C(=O)NC(C(C)O)C(=O)NC(CC9=CC=CC=C9)C(=O)NC(CO)C(=O)NC(CC(=O)O)C(=O)O)C(=O)NC(CSSCC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NCC(=O)NCC(=O)N3)CC2=CC=CC=C2)CCSC)CC2=CC=C(C=C2)O)CCCNC(=N)N)NC(=O)CNC(=O)C(C)NC(=O)C(CCCCN)NC(=O)C(CC(=O)O)NC(=O)C(C(C)C)NC(=O)CN)C(=O)N2CCCC2C(=O)NC(C(=O)N1)CCCNC(=N)N)CC(=O)O)CC(=O)O)CC(=O)N)C(C)C)CO

1. The status of voltage-dependent calcium channels in alpha 1E knock-out mice

P T Toth, E C Lee, S M Wilson, D Ren, S E Gillard, L Tessarollo, N G Copeland, S Volsen, L H Philipson, N A Jenkins, R J Miller, S B Oh, C F Fletcher J Neurosci . 2000 Dec 1;20(23):8566-71. doi: 10.1523/JNEUROSCI.20-23-08566.2000.

It has been hypothesized that R-type Ca currents result from the expression of the alpha(1E) gene. To test this hypothesis we examined the properties of voltage-dependent Ca channels in mice in which the alpha(1E) Ca channel subunit had been deleted. Application of omega-conotoxin GVIA, omega-agatoxin IVA, and nimodipine to cultured cerebellar granule neurons from wild-type mice inhibited components of the whole-cell Ba current, leaving a "residual" R current with an amplitude of approximately 30% of the total Ba current. A minor portion of this R current was inhibited by the alpha(1E)-selective toxin SNX-482, indicating that it resulted from the expression of alpha(1E). However, the majority of the R current was not inhibited by SNX-482. The SNX-482-sensitive portion of the granule cell R current was absent from alpha(1E) knock-out mice. We also identified a subpopulation of dorsal root ganglion (DRG) neurons from wild-type mice that expressed an SNX-482-sensitive component of the R current. However as with granule cells, most of the DRG R current was not blocked by SNX-482. We conclude that there exists a component of the R current that results from the expression of the alpha(1E) Ca channel subunit but that the majority of R currents must result from the expression of other Ca channel alpha subunits.

2. Sex-dependent Cav2.3 channel contribution to the secondary hyperalgesia in a mice model of central sensitization

Raquel Tonello, Sérgio José Macedo-Júnior, Arthur Silveira Prudente, Débora Denardin Lückemeyer, Juliano Ferreira, Roberta Giusti Schran, Marcella Amorim Ferreira, Ana Merian Silva Brain Res . 2021 Aug 1;1764:147438. doi: 10.1016/j.brainres.2021.147438.

Central sensitization (CS) is characteristic of difficult to treat painful conditions, such as fibromyalgia and neuropathies and have sexual dimorphism involved. The calcium influx in nociceptive neurons is a key trigger for CS and the role of Cav2.1 and Cav2.2 voltage gated calcium channels (VGCC) in this role were evidenced with the use of ω-agatoxin IVA and ω-agatoxin MVIIA blockers, respectively. However, the participation of the α1 subunit of the voltage-gated channel Cav2.3, which conducts R-type currents, in CS is unknown. Furthermore, the role of sexual differences in painful conditions is still poorly understood. Thus, we investigated the role of Cav2.3 in capsaicin-induced secondary hyperalgesia in mice, which serve as a CS model predictive of the efficacy of novel analgesic drugs. Capsaicin injection in C57BL/6 mice caused secondary hyperalgesia from one to five hours after injection, and the effects were similar in male and female mice. In female but not male mice, intrathecal treatment with the Cav2.3 inhibitor SNX-482 partially and briefly reversed secondary hyperalgesia at a dose (300 pmol/site) that did not cause adverse effects. Moreover, Cav2.3 expression in the dorsal root ganglia (DRG) and spinal cord was reduced by intrathecal treatment with an antisense oligonucleotide (ASO) targeting Cav2.3 in female and male mice. However, ASO treatment was able to provide a robust and durable prevention of secondary hyperalgesia caused by capsaicin in female mice, but not in male mice. Thus, our results demonstrate that Cav2.3 inhibition, especially in female mice, has a relevant impact on a model of CS. Our results provide a proof of concept for Cav2.3 as a molecular target. In addition, the result associated to the role of differences in painful conditions linked to sex opens a range of possibilities to be explored and needs more attention. Thus, the relevance of testing Cav2.3 inhibition or knockdown in clinically relevant pain models is needed.

3. Boosting of synaptic potentials and spine Ca transients by the peptide toxin SNX-482 requires alpha-1E-encoded voltage-gated Ca channels

Bernardo L Sabatini, Andrew J Giessel PLoS One . 2011;6(6):e20939. doi: 10.1371/journal.pone.0020939.

The majority of glutamatergic synapses formed onto principal neurons of the mammalian central nervous system are associated with dendritic spines. Spines are tiny protuberances that house the proteins that mediate the response of the postsynaptic cell to the presynaptic release of glutamate. Postsynaptic signals are regulated by an ion channel signaling cascade that is active in individual dendritic spines and involves voltage-gated calcium (Ca) channels, small conductance (SK)-type Ca-activated potassium channels, and NMDA-type glutamate receptors. Pharmacological studies using the toxin SNX-482 indicated that the voltage-gated Ca channels that signal within spines to open SK channels belong to the class Ca(V)2.3, which is encoded by the Alpha-1E pore-forming subunit. In order to specifically test this conclusion, we examined the effects of SNX-482 on synaptic signals in acute hippocampal slices from knock-out mice lacking the Alpha-1E gene. We find that in these mice, application of SNX-482 has no effect on glutamate-uncaging evoked synaptic potentials and Ca influx, indicating that that SNX-482 indeed acts via the Alpha-1E-encoded Ca(V)2.3 channel.