Productcode:N/A.Categories:Kv1.3channel,Potassiumchannels.Tag:Kv1.3.
AAsequence: Val-Gly-Ile-Asn-Val-Lys-Cys7-Lys-His-Ser-Arg-Gln-Cys13-Leu-Lys-Pro-Cys17-Lys-Asp-Ala-Gly-Met-Arg-Phe-Gly-Lys-Cys27-Thr-Asn-Gly-Lys-Cys32-His-Cys34-Thr-Pro-Lys-OH
Disulfidebondsbetween: Cys7-Cys27,Cys13-Cys32,Cys17-Cys34
Length(aa): 37
Formula: C169H281N57O46S7
MolecularWeight: 4071.90Da
Purityrate: >98%
Appearance:Whitelyophilizedsolid
Solubility: waterandsalinebuffer
CASnumber: notavailable
Source: Synthetic
ThepotassiumchannelKv1.3isanattractivepharmacologicaltargetforimmunomodulationofTcell-mediatedautoimmunediseases.PotentandselectiveblockersofKv1.3arepotentialtherapeuticsfortreatingthesediseases.HerewedescribethedesignofanewpeptideinhibitorthatispotentandselectiveforKv1.3.Threeresidues(Gly(11),Ile(28),andAsp(33))ofascorpiontoxinBmKTXweresubstitutedbyArg(11),Thr(28),andHis(33),resultinginanewpeptide,namedADWX-1.TheADWX-1peptideblockedKv1.3withpicomolaraffinity(IC(50),1.89pM),showinga100-foldincreaseinactivitycomparedwiththenativeBmKTXtoxin.TheADWX-1alsodisplayedgoodselectivityonKv1.3overrelatedKv1.1andKv1.2channels.Fur
Thermore,alanine-scanningmutagenesiswascarriedouttomapthefunctionalresiduesofADWX-1inblockingKv1.3.Moreover,computationalsimulationwasusedtobuildastructuralmodeloftheADWX-1-Kv1.3complex.ThismodelsuggeststhatallmutatedresiduesarefavorableforboththehighpotencyandselectivityofADWX-1towardKv1.3.WhileArg(11)ofADWX-1interactswithAsp(386)inKv1.3,Thr(28)andHis(33)ofADWX-1locaterightabovetheselectivityfilter-S6linkerofKv1.3.Together,ourdataindicatethatthespecificADWX-1peptidewouldbeaviableleadinthetherapyofTcell-mediatedautoimmunediseases,andthesuccessfuldesignofADWX-1suggeststhatrationaldesignbasedonthestructuralmodelofthepeptide-channelcomplexshouldacceleratethedevelopmentofdiagnosticandtherapeuticagentsforhumanchannelopathies.
SongHan,etal.(2008)StructuralBasisofaPotentPeptideInhibitorDesignedforKv1.3Channel,aTherapeuticTargetofAutoimmuneDisease.JBCPMID:18480054
SelectiveinhibitionofCCR7(-)effectormemoryTcellactivationbyanovelpeptidetargetingKv1.3channelinaratexperimentalautoimmuneencephalomyelitismodel.
Thevoltage-gatedKv1.3K(+)channelineffectormemoryTcellsservesasanewtherapeutictargetformultiplesclerosis.Inourpreviousstudies,thenovelpeptideADWX-1wasdesignedandsynthesizedasaspecificKv1.3blocker.However,itisunclearifandhowADWX-1alleviatesexperimentalautoimmuneencephalomyelitis,amodelformultiplesclerosis.Inthisstudy,theadmi
NISTrationofADWX-1significantlyamelioratedtheratexperimentalautoimmuneencephalomyelitismodelbyselectivelyinhibitingCD4(+)CCR7(-)phenotypeeffectormemoryTcellactivation.Incontrast,theKv1.3-specificpeptidehadlittleeffectonCD4(+)CCR7(+)cells,therebylimitingsideeffects.Furthermore,wedeterminedthatADWX-1isinvolvedintheregulationofNF-κBsignalingthroughupstreamproteinkinaseC-θ(PKCθ)intheIL-2pathwayofCD4(+)CCR7(-)cells.TheelevatedexpressionofKv1.3mRNAandproteininactivatedCD4(+)CCR7(-)cellswasreducedbyADWX-1engagement;however,anapparentalterationinCD4(+)CCR7(+)cellswasnotobserved.Moreover,theselectiveregulationoftheKv1.3channelgeneexpressionpatternbyADWX-1providedafurtherandsustainedinhibitionoftheCD4(+)CCR7(-)phenotype,whichdependsontheactivityofKv1.3tomodulateitsactivationsignal.Inaddition,ADWX-1mediatedtheactivationofdifferentiatedTh17cellsthroughtheCCR7(-)phenotype.TheefficacyofADWX-1issupportedbymultiplefunctions,whicharebasedonaKv1.3(high)CD4(+)CCR7(-)Tcellselectivitythroughtwodifferentpathways,includingtheclassicchannelactivity-associatedIL-2pathwayandthenewKv1.3channelgeneexpressionpathway.
ZhiLi,etal.(2012)SelectiveInhibitionofCCR7−EffectorMemoryTCellActivationbyaNovelPeptideTargetingKv1.3ChannelinaRatExperimentalAutoimmuneEncephalomyelitisModel.JBCPMID:22761436
DifferentresiduesinchannelturretdeterminingtheselectivityofADWX-1inhibitorpeptidebetweenKv1.1andKv1.3channels.
ThelowselectivityofKv1peptideinhibitorsforspecificisoformsmakesthempoorcandidatesforthedevelopmentoftheraputics.Usingcombinedapproaches,weshowedthattheKv1turretisthecriticaldeterminantforADWX-1peptideinhibitorselectivityofKv1.3overKv1.1.MutationofKv1.1turretresiduestomatchthesequenceofKv1.3leadtoincreasedinhibitionofKv1.1activity.Thesestudiesmayleadtoimprovementsinpeptideinhibitordrugdevelopment.
YinSJ(2008)DifferentresiduesinchannelturretdeterminingtheselectivityofADWX-1inhibitorpeptidebetweenKv1.1andKv1.3channels.Journalofproteomeresearch PMID:18937510
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Smartox Biotechnology 是全球唯一一家专门生产动物毒液多肽毒素，用于细胞离子通道功能研究的生物医药公司。多肽毒素在生物制药领域具有重要的使用价值。Smartox Biotechnology 于 2009 年由来自 Grenoble 神经科学研究所 (Grenoble Institute of Neuroscience) 的 Michel de waard 博士创立, Smartox Biotechnology 专门研究动物毒液，制作合成多种毒液中的多肽成分（常称为毒素）。 De Waard 博士研究离子通道与毒素多肽的关系，尤其是鉴定、开发毒素多肽作为治疗性分子或细胞穿透肽 (cell penetrating peptides, CPP) 。其研究团队在毒液分离，药理性活性肽鉴定、富半胱氨酸肽定性、制作和优化等方面具有独特、丰富的经验。 2010 年， Smartox Biotechnolgy 被法国研究部 (Ministry of Research) 授予“新兴企业 OSEO 奖 (OSEO prize for emerging businesses) ”。
