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Huwentoxin IV

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

Huwentoxin IV is a selective NaV1.7 channel blocker with preference for neuronal NaV1.7, 1.2 and 1.3 (IC50 = 26, 150 and 338 nM, respectively). Huwentoxin IV inhibits the channel via binding at the neurotoxin receptor site 4 in the S3-S4 linker of domain II, trapping the voltage sensor in the inward, closed configuration.

Category

Peptide Inhibitors

Catalog number

BAT-010362

CAS number

526224-73-7

Molecular Formula

C174H278N52O51S6

Molecular Weight

4106.79

Specification
Reference Reading

IUPAC Name

(4S)-4-amino-5-[[(1R,4S,10S,13S,16S,19S,22S,25R,30R,33S,36S,39S,42S,45S,48S,51R,54S,57S,60S,63S,66S,69S,72R,77R,80S,83S,86S,89S,92S,95S)-30-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S,3S)-1-amino-3-methyl-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]carbamoyl]-42,60,69,92-tetrakis(4-aminobutyl)-4,16-bis(2-amino-2-oxoethyl)-22-(3-amino-3-oxopropyl)-89-benzyl-86-[(2S)-butan-2-yl]-36,45-bis(3-carbamimidamidopropyl)-83-(2-carboxyethyl)-19-(carboxymethyl)-39-[(1R)-1-hydroxyethyl]-13,48,63,66-tetrakis(hydroxymethyl)-33-(1H-indol-3-ylmethyl)-95-methyl-57,80-bis(2-methylpropyl)-2,3a,5,11,14,17,20,23,32,35,38,41,44,47,50,53,56,59,62,65,68,71,78,81,84,87,90,93,96-nonacosaoxo-54-propan-2-yl-a,27,28,74,75,99-hexathia-2a,3,6,12,15,18,21,24,31,34,37,40,43,46,49,52,55,58,61,64,67,70,79,82,85,88,91,94,97-nonacosazatetracyclo[49.46.4.225,72.06,10]trihectan-77-yl]amino]-5-oxopentanoic acid

Synonyms

HWTX-IV; H-Glu-Cys(1)-Leu-Glu-Ile-Phe-Lys-Ala-Cys(2)-Asn-Pro-Ser-Asn-Asp-Gln-Cys(3)-Cys(1)-Lys-Ser-Ser-Lys-Leu-Val-Cys(2)-Ser-Arg-Lys-Thr-Arg-Trp-Cys(3)-Lys-Tyr-Gln-Ile-NH2; L-alpha-glutamyl-L-cysteinyl-L-leucyl-L-alpha-glutamyl-L-isoleucyl-L-phenylalanyl-L-lysyl-L-alanyl-L-cysteinyl-L-asparagyl-L-prolyl-L-seryl-L-asparagyl-L-alpha-aspartyl-L-glutaminyl-L-cysteinyl-L-cysteinyl-L-lysyl-L-seryl-L-seryl-L-lysyl-L-leucyl-L-valyl-L-cysteinyl-L-seryl-L-arginyl-L-lysyl-L-threonyl-L-arginyl-L-tryptophyl-L-cysteinyl-L-lysyl-L-tyrosyl-L-glutaminyl-L-isoleucinamide (2->17),(9->24),(16->31)-tris(disulfide)

Appearance

White Lyophilized Solid

Purity

>99%

Sequence

ECLEIFKACNPSNDQCCKSSKLVCSRKTRWCKYQI (Disulfide bridge: Cys2 and Cys17, Cys9 and Cys24, Cys16 and Cys31)

Storage

Store at -20°C

Solubility

Soluble in Water

InChI

InChI=1S/C174H278N52O51S6/c1-13-87(9)135(138(185)243)223-149(254)106(51-54-128(182)234)201-152(257)110(68-92-45-47-94(232)48-46-92)206-144(249)100(39-22-27-59-177)198-162(267)122-80-280-282-82-124-167(272)220-123-81-281-279-79-121(217-140(245)96(180)49-55-131(237)238)164(269)205-108(65-84(3)4)151(256)202-107(52-56-132(239)240)150(255)224-136(88(10)14-2)170(275)210-111(67-91-33-16-15-17-34-91)153(258)195-98(37-20-25-57-175)141(246)193-89(11)139(244)216-120(165(270)211-115(71-130(184)236)172(277)226-64-32-44-126(226)168(273)215-119(77-230)160(265)208-113(70-129(183)235)155(260)209-114(72-133(241)242)156(261)200-105(147(252)218-124)50-53-127(181)233)78-278-283-83-125(221-169(274)134(86(7)8)222-157(262)109(66-85(5)6)204-143(248)99(38-21-26-58-176)196-158(263)116(74-227)213-161(266)118(76-229)212-146(251)101(199-163(123)268)40-23-28-60-178)166(271)214-117(75-228)159(264)197-103(42-30-62-190-173(186)187)142(247)194-102(41-24-29-61-179)148(253)225-137(90(12)231)171(276)203-104(43-31-63-191-174(188)189)145(250)207-112(154(259)219-122)69-93-73-192-97-36-19-18-35-95(93)97/h15-19,33-36,45-48,73,84-90,96,98-126,134-137,192,227-232H,13-14,20-32,37-44,49-72,74-83,175-180H2,1-12H3,(H2,181,233)(H2,182,234)(H2,183,235)(H2,184,236)(H2,185,243)(H,193,246)(H,194,247)(H,195,258)(H,196,263)(H,197,264)(H,198,267)(H,199,268)(H,200,261)(H,201,257)(H,202,256)(H,203,276)(H,204,248)(H,205,269)(H,206,249)(H,207,250)(H,208,265)(H,209,260)(H,210,275)(H,211,270)(H,212,251)(H,213,266)(H,214,271)(H,215,273)(H,216,244)(H,217,245)(H,218,252)(H,219,259)(H,220,272)(H,221,274)(H,222,262)(H,223,254)(H,224,255)(H,225,253)(H,237,238)(H,239,240)(H,241,242)(H4,186,187,190)(H4,188,189,191)/t87-,88-,89-,90+,96-,98-,99-,100-,101-,102-,103-,104-,105-,106-,107-,108-,109-,110-,111-,112-,113-,114-,115-,116-,117-,118-,119-,120-,121-,122-,123-,124-,125-,126-,134-,135-,136-,137-/m0/s1

InChI Key

MJMLBAPXMAOKDU-DXFBXFEISA-N

Canonical SMILES

CCC(C)C1C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC2CSSCC3C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(CSSCC(C(=O)NC(CSSCC(C(=O)NC(C(=O)NC(C(=O)N1)CCC(=O)O)CC(C)C)NC(=O)C(CCC(=O)O)N)C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)N3)C(C)C)CC(C)C)CCCCN)CO)CO)CCCCN)NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C4CCCN4C(=O)C(NC2=O)CC(=O)N)CO)CC(=O)N)CC(=O)O)CCC(=O)N)C(=O)NC(CCCCN)C(=O)NC(CC5=CC=C(C=C5)O)C(=O)NC(CCC(=O)N)C(=O)NC(C(C)CC)C(=O)N)CC6=CNC7=CC=CC=C76)CCCNC(=N)N)C(C)O)CCCCN)CCCNC(=N)N)CO)C)CCCCN)CC8=CC=CC=C8

1. Structures of human Nav1.7 channel in complex with auxiliary subunits and animal toxins

Kun Wu, Dongliang Liu, Nieng Yan, Huaizong Shen, Jianlin Lei Science . 2019 Mar 22;363(6433):1303-1308. doi: 10.1126/science.aaw2493.

Voltage-gated sodium channel Nav1.7 represents a promising target for pain relief. Here we report the cryo-electron microscopy structures of the human Nav1.7-β1-β2 complex bound to two combinations of pore blockers and gating modifier toxins (GMTs), tetrodotoxin with protoxin-II and saxitoxin with huwentoxin-IV, both determined at overall resolutions of 3.2 angstroms. The two structures are nearly identical except for minor shifts of voltage-sensing domain II (VSDII), whose S3-S4 linker accommodates the two GMTs in a similar manner. One additional protoxin-II sits on top of the S3-S4 linker in VSDIVThe structures may represent an inactivated state with all four VSDs "up" and the intracellular gate closed. The structures illuminate the path toward mechanistic understanding of the function and disease of Nav1.7 and establish the foundation for structure-aided development of analgesics.

2. Tarantula huwentoxin-IV inhibits neuronal sodium channels by binding to receptor site 4 and trapping the domain ii voltage sensor in the closed configuration

Theodore R Cummins, Jon-Paul Bingham, Edward Moczydlowski, Weiguo Zhu, Songping Liang, Yucheng Xiao J Biol Chem . 2008 Oct 3;283(40):27300-13. doi: 10.1074/jbc.M708447200.

Peptide toxins with high affinity, divergent pharmacological functions, and isoform-specific selectivity are powerful tools for investigating the structure-function relationships of voltage-gated sodium channels (VGSCs). Although a number of interesting inhibitors have been reported from tarantula venoms, little is known about the mechanism for their interaction with VGSCs. We show that huwentoxin-IV (HWTX-IV), a 35-residue peptide from tarantula Ornithoctonus huwena venom, preferentially inhibits neuronal VGSC subtypes rNav1.2, rNav1.3, and hNav1.7 compared with muscle subtypes rNav1.4 and hNav1.5. Of the five VGSCs examined, hNav1.7 was most sensitive to HWTX-IV (IC(50) approximately 26 nM). Following application of 1 microm HWTX-IV, hNav1.7 currents could only be elicited with extreme depolarizations (>+100 mV). Recovery of hNav1.7 channels from HWTX-IV inhibition could be induced by extreme depolarizations or moderate depolarizations lasting several minutes. Site-directed mutagenesis analysis indicated that the toxin docked at neurotoxin receptor site 4 located at the extracellular S3-S4 linker of domain II. Mutations E818Q and D816N in hNav1.7 decreased toxin affinity for hNav1.7 by approximately 300-fold, whereas the reverse mutations in rNav1.4 (N655D/Q657E) and the corresponding mutations in hNav1.5 (R812D/S814E) greatly increased the sensitivity of the muscle VGSCs to HWTX-IV. Our data identify a novel mechanism for sodium channel inhibition by tarantula toxins involving binding to neurotoxin receptor site 4. In contrast to scorpion beta-toxins that trap the IIS4 voltage sensor in an outward configuration, we propose that HWTX-IV traps the voltage sensor of domain II in the inward, closed configuration.

3. Development of Photocrosslinking Probes Based on Huwentoxin-IV to Map the Site of Interaction on Nav1.7

Christopher M Koth, Natalie Garcia, Hui Xu, Christine Kugel, Jian Payandeh, Edward W Tate, Tianbo Li, Foteini Tzakoniati Cell Chem Biol . 2020 Mar 19;27(3):306-313.e4. doi: 10.1016/j.chembiol.2019.10.011.

Voltage-gated sodium (Nav) channels respond to changes in the membrane potential of excitable cells through the concerted action of four voltage-sensor domains (VSDs). Subtype Nav1.7 plays an important role in the propagation of signals in pain-sensing neurons and is a target for the clinical development of novel analgesics. Certain inhibitory cystine knot (ICK) peptides produced by venomous animals potently modulate Nav1.7; however, the molecular mechanisms underlying their selective binding and activity remain elusive. This study reports on the design of a library of photoprobes based on the potent spider toxin Huwentoxin-IV and the determination of the toxin binding interface on VSD2 of Nav1.7 through a photocrosslinking and tandem mass spectrometry approach. Our Huwentoxin-IV probes selectively crosslink to extracellular loop S1-S2 and helix S3 of VSD2 in a chimeric channel system. Our results provide a strategy that will enable mapping of sites of interaction of other ICK peptides on Nav channels.