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FluorescentNav1.7blockerCy5-ProTx-IIisafluorescentlylabeledProTx-II,afamousNav1.7blocker.ThewildtypeProTx-IIblocksNav1.7 withanIC50 valueofaround300pM,Nav1.2, Nav1.5and Nav1.6 withIC50 valuesof41nM,79nMand26nMrespectively.TheCy5-ProTx-IIversiondevelopedbySmartoxhaspotentNav1.7blockingactivity.ItwasshowntofullyblockNav1.7at100nMconcentration.A,Recordingtracesoftransiently-expressedhumanNav1.7currentinthepresenceofCy5-ProTx-II(100nM).Thecurrentwaselicitedbya50ms-depolarizingpulseto-10mVfromaholdingpotentialof-90mV.Inter-sweepperiodwas10s.Currentamplitudeswereplottedagainsttime.Notethattoxin-inducedinhibitionisresistanttowashout,howeveritcanbepartiallyrelievedbydepolarizingthecellmembraneatthetimepointindicatedbytheredbar.B,C,RecordingtracesofhNav1.7currentinthepresenceofCy5-ProTx-II(100nM)fromtwodistinctcells.Membranedepolarizationfailstorelievetheinhibitioninthepresenceof100nMCy5-ProTx-II;howevertheinhibitioncanbepartiallyrelievedbydepolarizationafterwashout.D,FamiliesofhNav1.7currenttracesincontrolandinthepresenceof100nMCy5-ProTx-II.Currentswereevokedbydepolarizingpulsesfrom-60mVto40mV,whilethecellwasholdat-90mV.E,Amplitude-voltagerelationshipsobtainedfromD.Description:Productcode:N/A.Category:Sodiumchannels.Tags:Nav1.7,protoxin,protx.AAsequence: Tyr-Cys2-Gln-Lys-Trp-Met-Trp-Thr-Cys9-Asp-Ser-Glu-Arg-Lys-Cys15-Cys16-Glu-Gly-Met-Val-Cys21-Arg-Leu-Trp-Cys25-Lys-Lys-Lys-Leu-Trp-OHDisulfidebonds: Cys2-Cys16,Cys9-Cys21,Cys15-Cys25Length(aa): 30ProTx-IIformula: C168H250N46O41S8MolecularWeight:closeto4450g/molAppearance:darklyophilizedsolidSource: SyntheticPurityrate: >95%Cy5:λex646nm,λem662nmStoichiometry:1:1Reference:Spider-venompeptidesthattargetvoltage-gatedsodiumchannels:pharmacologicaltoolsandpotentialtherapeuticleadsVoltage-gatedsodium(Na(V))channelsplayacentralroleinthepropagationofactionpotentialsinexcitablecellsinbothhumansandinsects.ManyvenomousanimalshavethereforeevolvedtoxinsthatmodulatetheactivityofNa(V)channelsinordertosuBDuetheirpreyanddeterpredators.SpidervenomsinparticulararerichinNa(V)channelmodulators,withone-thirdofallknownionchanneltoxinsfromspidervenomsactingonNa(V)channels.Herewereviewthelandscapeofspider-venompeptidesthathavesofarbeendescribedtotargetvertebrateorinvertebrateNa(V)channels.Thesepeptidesfallinto12distinctfamiliesbasedontheirprimarystructureandcysteinescaffold.Someofthesepeptideshavebecomeusefulpharmacologicaltools,whileothershavepotentialastherapeuticleadsbecausetheytargetspecificNa(V)channelsubtypesthatareconsideredtobeimportantanalgesictargets.Spidervenomsareconservativelypredictedtocontainmorethan10millionbioactivepeptidesandsofaronly0.01%ofthisdiversitybeencharacterised.Thus,itislikelythatfutureresearchwillrevealadditionalstructuralclassesofspider-venompeptidesthattargetNa(V)channels.KlintJK., etal. (2012)Spider-venompeptidesthattargetvoltage-gatedsodiumchannels:pharmacologicaltoolsandpotentialtherapeuticleads. Toxicon. PMID:22543187EvidenceformultipleeffectsofProTxIIonactivationgatinginNa(V)1.5ThepeptidetoxinProTxII,recentlyisolatedfromthevenomofthetarantulaspiderThrixopelmapruriens,modifiesgatinginvoltage-gatedNa+andCa2+channels.ProTxIIisdistinctfromotherknownNa+channelgatingmodifiertoxinsinthatitaffectsactivation,butnotinactivation.Itshiftsactivationgatingpositivelyanddecreasescurrentmagnitudesuchthatthedose-dependenceoftoxinactionmeasuredatasinglepotentialreflectsbotheffects.Totesttheextenttowhichtheseeffectswereindependent,wetrackedseveraldifferentmeasuresofcurrentamplitude,voltage-dependentactivation,andcurrentkineticsinNa(V)1.5inarangeoftoxinconcentrations.ChangesinvoltagedependenceandadecreaseinG(max)appearedatrelativelylowconcentrations(40-100nM)whileapositiveshiftinthevoltagerangeofactivationwasapparentathighertoxinconcentrations(>or=500nM).BecauseProTxIIcarriesanet+4chargewetestedwhetherelectrostaticinteractionscontributedtotoxinaction.WeexaminedtheeffectsofProTxIIinthepresenceofhighextracellularBa2+,knowntoscreenand/orbindtosurfacecharge.Some,butnotallaspectsofProTxIImodificationweresensitivetothepresenceofBa2+indicatingthecontributionofanelectrostatic,surfacecharge-likemechanismandsupportingtheideaofamulti-facetedtoxin-channelinteraction.EdgertonG.B., etal. (2008)EvidenceformultipleeffectsofProTxIIonactivationgatinginNa(V)1.5, Toxicon. PMID:18657562ProTx-II,aselectiveinhibitorofNav1.7sodiumchannels,blocksactionpotentialpropagationinnociceptorsVoltage-gatedsodium(Na(V)1)channelsplayacriticalroleinmodulatingtheexcitABIlityofsensoryneurons,andhumangeneticevidencepointstoNa(V)1.7asanessentialcontributortopainsignaling.Humanloss-of-functionmutationsinSCN9A,thegeneencodingNa(V)1.7,causechannelopathy-associatedindifferencetopain(CIP),whereasgain-of-functionmutationsareassociatedwithtwoinheritedpainfulneuropathies.AlthoughthehumangeneticdatamakeNa(V)1.7anattractivetargetforthedevelopmentofanalgesics,pharmacologicalproof-of-conceptinexperimentalpainmodelsrequiresNa(V)1.7-selectivechannelblockers.Here,weshowthatthetarantulavenompeptideProTx-IIselectivelyinteractswithNa(V)1.7channels,inhibitingNa(V)1.7withanIC(50)valueof0.3nM,comparedwithIC(50)valuesof30to150nMforotherheterologouslyexpressedNa(V)1subtypes.ThissubtypeselectivitywasabolishedbyapointmutationinDIIS3.ItisinterestingthatapplicationofProTx-IItodesheathedcutaneousnervescompletelyblockedtheC-fibercompoundactionpotentialatconcentrationsthathadlittleeffectonAbeta-fiberconduction.ProTx-IIapplicationhadlittleeffectonactionpotentialpropagationoftheintactnerve,whichmayexplainwhyProTx-IIwasnotefficaciousinrodentmodelsofacuteandinflammatorypain.Mono-iodo-ProTx-II((125)I-ProTx-II)bindswithhighaffinity(K(d)=0.3nM)torecombinanthNa(V)1.7channels.Bindingof(125)I-ProTx-IIisinsensitivetothepresenceofotherwellcharacterizedNa(V)1channelmodulators,suggestingthatProTx-IIbindstoanovelsite,whichmaybemoreconducivetoconferringsubtypeselectivitythanthesiteoccupiedbytrADItionallocalanestheticsandanticonvulsants.Thus,the(125)I-ProTx-IIbindingassay,describedhere,offersanewtoolinthesearchfornovelNa(V)1.7-selectiveblockers.WilliamA., etal.(2007)ProTx-II,aselectiveinhibitorofNav1.7sodiumchannels,blocksactionpotentialpropagationinnociceptors. Mol.Pharm. PMID:18728100ProTx-IandProTx-II:gatingmodifiersofvoltage-gatedsodiumchannelsThetarantulavenompeptidesProTx-IandProTx-IIinhibitvoltage-gatedsodiumchannelsbyshiftingtheirvoltagedependenceofactivationtoamorepositivepotential,thusactingbyamechanismsimilartothatofpotassiumchannelgatingmodifierssuchashanatoxinandVSTX1.ProTx-IandProTx-IIinhibitallsodiumchannel(Nav1)subtypestestedwithsimilarpotencyandrepresentthefirstpotentpeptidylinhibitorsofTTX-resistantsodiumchannels.Likegatingmodifiersofpotassiumchannels,ProTx-IandProTx-IIconformtotheinhibitorycystineknotmotif,andProTx-IIwasdemonstratedtobindtosodiumchannelsintheclosedstate.Bothtoxinshavebeensynthesizedchemically,andProTx-II,producedbyrecombinantmeans,hasbeenusedtomaptheinteractionsurfaceofthepeptidewiththeNav1.5channel.Incomparison,beta-scorpiontoxinsactivatesodiumchannelsbyshiftingthevoltagedependenceofactivationtomorenegativepotentials,andtogetherthesepeptidesrepresentvaluabletoolsforexploringthegatingmechanismofsodiumchannels.PriestB.T., etal.(2007)ProTx-IandProTx-II:gatingmodifiersofvoltage-gatedsodiumchannels, Toxicon. PMID:17087985Differentialphospholipidbindingbysite3andsite4toxins.Implicationsforstructuralvariabilitybetweenvoltage-sensitivesodiumchanneldomainsIthasbeenshownrecentlythatpolypeptidetoxinsthatmodulatethegatingpropertiesofvoltage-sensitivecationchannelsareabletobindtophospholipidmembranes,leadingtothesuggestionthatthesetoxinsareabletoaccessachannel-bindingsitethatremainsmembrane-restricted(Lee,S.-Y.,andMacKinnon,R.(2004)Nature430,232-235).WethereforeexaminedtheabilityofanthopleurinB(ApB),aseaanemonetoxinthatselectivelymodifiesinactivationkineticsofNa(V)1.xchannels,andProTx-II,aspidertoxinthatmodifiesactivationkineticsofthesamechannels,tobindtoliposomes.WhereasProTx-IIcanbequantitativelydepletedfromsolutionuponincubationwithphosphatidylcholine/phosphatidylserineliposomes,ApBdisplaysnodiscernIBLephospholipidbindingactivity.Wethereforeexaminedtheactivitiesofstructurallyunrelatedsite3andsite4toxinsderivedfromLeiurusandCentruroidesvenoms,respectively,inthesameassay.LikeApB,thesite3toxinLqqVshowsnolipidbindingactivity,whereasthesite4toxinCentruroidestoxinII,likeProTx-II,iscompletelybound.WeconcludethattoxinsthatmodifyinactivationkineticsviabindingtoNa(V)1.xsite3lacktheabilitytobindphospholipids,whereassite4toxins,whichmodifyactivation,havethisactivity.ThisinherentdifferencesuggeststhattheconformationofdomainIImorecloselyresemblesthatoftheK(V)APchannelthandoestheconformationofdomainIV.SmithJ.J., etal. (2005)Differentialphospholipidbindingbysite3andsite4toxins.Implicationsforstructuralvariabilitybetweenvoltage-sensitivesodiumchanneldomains, JBiolChem. PMID:15632158TwotarantulapeptidesinhibitactivationofmultiplesodiumchannelsTwopeptides,ProTx-IandProTx-II,fromthevenomofthetarantulaThrixopelmapruriens,havebeenisolatedandcharacterized.Thesepeptideswerepurifiedonthebasisoftheirabilitytoreversiblyinhibitthetetrodotoxin-resistantNachannel,Na(V)1.8,andareshowntobelongtotheinhibitorycystineknot(ICK)familyofpeptidetoxinsinteractingwithvoltage-gatedionchannels.Thefamilyhasseveralhallmarks:cystinebridgeconnectivity,mechanismofchannelinhibition,andpromiscuityacrosschannelswithinandacrosschannelfamilies.ThecystinebridgeconnectivityofProTx-IIisverysimilartothatofothermembersofthisfamily,i.e.,C(2)toC(16),C(9)toC(21),andC(15)toC(25).Thesepeptidesarethefirsthigh-affinityligandsfortetrodotoxin-resistantperipheralnerveNa(V)channels,butalsoinhibitotherNa(V)channels(IC(50)’s<100nM).ProTx-IandProTx-IIshiftthevoltagedependenceofactivationofNa(V)1.5tomorepositivevoltages,similartoothergating-modifierICKfamilymembers.ProTx-IalsoshiftsthevoltagedependenceofactivationofCa(V)3.1(alpha(1G),T-type,IC(50)=50nM)withoutaffectingthevoltagedependenceofinactivation.Toenablefurtherstructuralandfunctionalstudies,syntheticProTx-IIwasmade;itadoptsthesamestructureandhasthesamefunctionalpropertiesasthenativepeptide.SyntheticProTx-Iwasalsomadeandexhibitsthesamepotencyasthenativepeptide.SyntheticProTx-I,butnotProTx-II,alsoinhibitsK(V)2.1channelswith10-foldlesspotencythanitspotencyonNa(V)channels.ThesepeptidesrepresentnoveltoolsforexploringthegatingmechanismsofseveralNa(V)andCa(V)channels.MiddletonR.E., etal. (2002)Twotarantulapeptidesinhibitactivationofmultiplesodiumchannels, Biochemistry. PMID:12475222

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) ”。 

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