SelectiveantagoNISTofthealpha(1A)-adrenoceptor
AdTx1(rho-Da1a–ρ-Da1a)isa65amino-acidpeptideoriginallyisolatedfromthevenomofthegreenmamba,anAfricansnake(Dendroaspisangusticep).AdTx1isstABIlizedbyfourdisulfidebridgesandbelongstothefamilyofthethree-finger-foldpeptide.AdTx1hassubnanomolaraffinity(K(i)=0.35nM)andhighspecificityforthehumanalpha(1A)-adrenoceptorsubtypeandis1000timesmorepotentonthissubtypethanonotheradrenoceptorsubtypes.AdTx1isapotentrelaxantofsmoothmuscles.
Description:
AAsequence:LTC3VTSKSIFGITTEDC17PDGQNLC24FKRRHYVVPKIYDSTRGC42AATC46PIPENYDSIHC57C58KTDKC63NE
Disulfidebonds:Cys3-Cys24,Cys17-Cys42,Cys46-Cys57,Cys58-Cys63
Length(aa):65
Formula:C310H481N87O100S8
MolecularWeight(average): 7283.29Da
Appearance:<hitelyophilizedsolid
Solubility: waterandsalinebuffer
CASnumber: notavailable
Source:synthetic
Purityrate: >98%
Reference:
IsolationandpharmacologicalcharacterizationofAdTx1,anaturalpeptidedisplayingspecificinsurmountableantagonismofthea1A-adrenoceptor
Abstract:
Venomsarearichsourceofligandsforionchannels,butverylittleisknownabouttheircapacitytomodulateG-proteincoupledreceptor(GPCR)activity.WedevelopedastrategytoidentifynoveltoxinstargetingGPCRs.Westudiedtheinteractionsofmambavenomfractionswithalpha(1)-adrenoceptorsinbindingexperimentswith(3)H-prazosin.Theactivepeptide(AdTx1)wassequencedbyEdmandegradationandmassspectrometryfragmentation.Itssynthetichomologuewaspharmacologicallycharacterizedbybindingexperimentsusingclonedreceptorsandbyfunctionalexperimentsonrabbitisolatedprostaticsmoothmuscle.AdTx1,a65amino-acidpeptidestabilizedbyfourdisulphidebridges,belongstothethree-finger-foldpeptidefamily.Ithassubnanomolaraffinity(K(i)=0.35nM)andhighspecificityforthehumanalpha(1A)-adrenoceptorsubtype.Weshowedhighselectivityandaffinity(K(d)=0.6nM)ofrADIo-labelledAdTx1indirectbindingexperimentsandrevealedaslowassociationconstant(k(on)=6x10(6).M(-1).min(-1))withanunusuallystablealpha(1A)-adrenoceptor/AdTx1complex(t(1/2diss)=3.6h).AdTx1displayedpotentinsurmountableantagonismofphenylephrine’sactionsinvitro(rabbitisolatedprostaticmuscle)atconcentrationsof10to100nM.AdTx1isthemostspecificandselectivepeptideinhibitorforthealpha(1A)-adrenoceptoridentifiedtodate.Itdisplaysinsurmountableantagonism,actingasapotentrelaxantofsmoothmuscle.Itspeptidicnaturecanbeexploitedtodevelopnewtools,asaradio-labelled-AdTx1orafluoro-labelled-AdTx1.IdentificationofAdTx1thusoffersnewperspectivesfordevelopingnewdrugsfortreatingbenignprostatichyperplasia.
Gprotein-coupledreceptors,anunexploitedanimaltoxintargets:Explorationofgreenmambavenomfornoveldrugcandidatesactiveagainstadrenoceptors
Abstract:
AtatimewhenpharmaceuticalcompaniesarehavingtroublefindingnewlowMWdrugsandwhenBIOLOGicsarebecomingmorecommon,animalvenomscouldconstituteanunderexploitedsourceofnoveldrugcandidates.WelookedforidentifyingnovelanimaltoxinsactiveagainstGprotein-coupledreceptors(GPCR),themostfrequentlyexploitedclassoftreatmenttargets,withtheaimtodevelopnovelresearchtoolsanddrugcandidates.Screeningofgreenmamba(Dendroaspisangusticeps)venomagainstadrenoceptorsidentifiedtwonovelvenompeptides.ρ-Da1ashownanaffinityof0.35 nMfortheα1a-ARwhileρ-Da1bdisplayedaffinitiesbetween14and73 nMforthethreeα2-ARs.Thesetwovenompeptideshavesequencessimilartothoseofmuscarinictoxinsandbelongtothethree-finger-foldproteinfamily.α1a-ARistheprimarytargetforthetreatmentofprostatehypertrophy.Invitroandinvivotestsdemonstratedthatρ-Da1areducedprostaticmuscletoneasefficientlyastamsulosin(anantagonistpresentlyused),butwithfewercardiovascularsideeffects.α2-ARsaretheprototypeofGPCRsnotcurrentlyusedastreatmenttargetsduetoalackofspecificligands.Blockageofthesereceptorsincreasesintestinalmotility,whichmaybecompromisedbyaBDominalsurgeryandreducesorthosterichypotension.Invitroandinvivotestsdemonstratedthatρ-Da1bantagonizesα2-ARsinsmoothmusclesandincreasedheartrateandbloodcatecholamineconcentrations.TheseresultshighlightpossIBLeexploitationofρ-Da1aandρ-Da1binimportantpathologies.
Crystallizationofrecombinantgreenmambaρ-Da1atoxinduringalyophilizationprocedureanditsstructuredetermination
MaïgaA.,etal.(2013)Crystallizationofrecombinantgreenmambaρ-Da1atoxinduringalyophilizationprocedureanditsstructuredetermination.ActaCrystallogrSectFStructBiolCrystCommun.PMID:23722859
Abstract:
ρ-Da1atoxinfromeasterngreenmamba(Dendroaspisangusticeps)venomisapolypeptideof65aminoacidswithastrongaffinityfortheG-protein-coupledα(1A)-adrenoceptor.Thisneurotoxinhasbeencrystallizedfromresolubilizedlyophilizedpowder,butthebestcrystalsgrewspontaneouslyduringlyophilization.ThecrystalsbelongedtothetrigonalspacegroupP3(1)21,withunit-cellparametersa=b=37.37,c=66.05Å,anddiffractedto1.95Åresolution.Thestructuresolvedbymolecularreplacementshowedstrongsimilaritiestogreenmambamuscarinictoxins.
Effectsofρ-Da1aapeptidicα(1)(A)-adrenoceptorantagonistinhumanisolatedprostaticadenomaandanaesthetizedrats
Abstract
ρ-Da1a,a65amino-acidpeptide,hassubnanomolaraffinityandhighselectivityforthehumanα(1)(A)-adrenoceptorsubtype.Thepurposeofthisstudywastocharacterizethepharmacologicaleffectsofρ-Da1aonprostaticfunction,bothinvivoandinvitro.ρ-Da1awastestedasanantagonistofadrenaline-inducedeffectsonCOScellstransfectedwiththehumanα(1)(A)-adrenoceptoraswellasonhumanisolatedprostaticadenomaobtainedfrompatientssufferingfrombenignprostatichyperplasia.Moreover,wecomparedtheeffectsofρ-Da1aandtamsulosinonphenylephrine(PHE)-inducedincreasesinintra-urethral(IUP)andarterialpressures(AP)inanaesthetizedrats,followingi.v.orp.o.administration.OnCOScellsexpressinghumanα(1)(A)-adrenoceptorsandonhumanprostaticstrips,ρ-Da1ainhibitedadrenaline-andnoradrenaline-inducedeffects.Inanaesthetizedrats,ρ-Da1aandtamsulosinadministeredi.v.30 minbeforePHEsignificantlyantagonizedtheeffectsofPHEonIUP.ThepK(B)valuesfortamsulosinandρ-Da1aforthiseffectweresimilar.WithregardstoAP,ρ-Da1aonlyreducedtheeffectofPHEonAPatthelowestdosetested(10 μg·kg(-1)),whereastamsulosinsignificantlyreducedPHEeffectsatdosesbetween10and150 μg·kg(-1).ρ-Da1aexhibitedarelevanteffectonIUPandasmalleffectonAP.Incontrast,tamsulosinantagonizedtheeffectsofPHEonbothIUPandAP.Weconcludethatρ-Da1aismoreuroselectivethantamsulosin.ρ-Da1aisthemostselectivepeptidicantagonistforα(1A)-adenoceptorsidentifiedtodateandcouldbeanewtreatmentforvariousurologicaldiseases.
Orthostericbindingofρ-Da1a,anaturalpeptideofsnakevenominteractingselectivelywiththeα1A-adrenoceptor
Abstract:
ρ-Da1aisathree-fingerfoldtoxinfromgreenmambavenomthatishighlyselectivefortheα1A-adrenoceptor.Thistoxinhasatypicalpharmacologicalproperties,includingincompleteinhibitionof(3)H-prazosinor(125)I-HEATbindingandinsurmountableantagonistaction.Weaimedtoclarifyitsmodeofactionattheα1A-adrenoceptor.Theaffinity(pKi9.26)andselectivityofρ-Da1afortheα1A-adrenoceptorwereconfirmedbycomparingbindingtohumanadrenoceptorsexpressedineukaryoticcells.Equilibriumandkineticbindingexperimentswereusedtodemonstratethatρ-Da1a,prazosinandHEATcompeteattheα1A-adrenoceptor.ρ-Da1adidnotaffectthedissociationkineticsof(3)H-prazosinor(125)I-HEAT,andtheIC50ofρ-Da1a,determinedbycompetitionexperiments,increasedlinearlywiththeconcentrationofradioligandsused,whiletheresidualbindingbyρ-Da1aremainedstable.Theeffectofρ-Da1aonagonist-stimulatedCa(2+)releasewasinsurmountableinthepresenceofphenethylamine-orimidazoline-typeagonists.Tenmutationsintheorthostericbindingpocketoftheα1A-adrenoceptorwereevaluatedforalterationsinρ-Da1aaffinity.TheD106(3.32)AandtheS188(5.42)A/S192(5.46)Areceptormutationsreducedtoxinaffinitymoderately(6and7.6times,respectively),whiletheF86(2.64)A,F288(6.51)AandF312(7.39)Amutationsdiminisheditdramaticallyby18-to93-fold.Inaddition,residueF86(2.64)wasidentifiedasakeyinteractionpointfor(125)I-HEAT,asthevariantF86(2.64)Ainduceda23-foldreductioninHEATaffinity.UnliketheM1muscarinicacetylcholinereceptortoxinMT7,ρ-Da1ainteractswiththehumanα1A-adrenoceptororthostericpocketandsharesreceptorinteractionpointswithantagonist(F86(2.64),F288(6.51)andF312(7.39))andagonist(F288(6.51)andF312(7.39))ligands.Itsselectivityfortheα1A-adrenoceptormayresult,atleastpartly,fromitsinteractionwiththeresidueF86(2.64),whichappearstobeimportantalsoforHEATbinding.
Polypharmacologyprofilesandphylogeneticanalysisofthree-fingertoxinsfrommambavenom:caseofaminergictoxins
Compositionofmamba’svenomisquiteatypicalandcharacterizedbythepresenceofalargediversityofthree-fingerfoldtoxins(3FTx)interactingwithvariousenzymes,receptorsandionchannels.Inparticular,3FTxfrommambasdisplaytheuniquepropertytointeractwithclassAGPCRs,sometimeswithahighaffinityandselectivity.Ascreeningoffiveofthesetoxins(MT1,MT3,MT7,ρ-Da1aandρ-Da1b)on29differentsubtypesofbioaminergicreceptors,usingcompetitionbindingexperiments,highlightsthediversityoftheirpharmacologicalprofiles.Thesetoxinsmaydisplayeitherabsoluteselectivityforonereceptorsubtypeorapolypharmacologicalpropertyforvariousbioaminergicreceptors.Nevertheless,adrenoceptoristhemainreceptorfamilytargetedbythesetoxins.FurThermore,anewreceptortargetwasidentifiedfor3FTxandtoxinsingeneral,theρ-Da1binteractingcompetitivelywiththehumandopamineD3receptorinthemicromolarrange.ThisresultexpandsthediversityofGPCRstargetedbytoxinsandmoregenerallyhighlightsthemultipotentinteractingpropertyof3FTx.Phylogenicanalyzesofthesetoxinsshowthatmuscarinic,adrenergicanddopaminergictoxinsmaybepooledinonefamilycalledaminergictoxins,thisfamilycomingprobablyfromaspecificradiationofligandspresentinmambavenoms.
Smartox Biotechnolgy的多肽毒素产品如下：
1. 作用于钠离子通道(Sodium channel)的毒素
Toxin name | Catalog # | Target |
Phrixotoxin-3 | 13PHX003 | Selective blocker of Nav1.2 |
µ-conotoxin GIIIB | CON020 | Selective blocker of Nav1.4 |
µ-conotoxin CnIIIC | CON021 | Selective blocker of Nav1.4 |
μ-conotoxin PIIIA | 08CON006 | Selective blocker of Nav1.4 |
Jingzhaotoxin-III | 12JZH003 | Selective blocker of Nav1.5 |
ProTx-II | 07PTX002 | Selective blocker of Nav1.7 |
ProTx-II Biotin | 12PTB002 | Selective blocker of Nav1.7 |
ProTx-I | 12PTX001 | Blocker of Nav1.8, Nav1.2, Nav1.5, Nav1.7 |
Huwentoxin-I | 07HWT001 | Blocker of TTX-S |
Huwentoxin-IV | 08HWT002 | Blocker of TTX-S |
Hainantoxin-III | 13HTX003 | Blocker of TTX-S |
Hainantoxin-IV | 12HTX001 | Blocker of TTX-S |
GsAF-I | 12GSF001 | Blocker of TTX-S |
GsAF-II | 12GSF002 | Blocker of TTX-S |
2. 作用于钾离子通道(Potassium channel)的毒素
Toxin name | Catalog # | Target |
KCa channels | ||
Apamin 蜜蜂神经毒素 | 08APA001 | SK1, SK2, SK3 |
Charybdotoxin 蝎毒素 | 11CHA001 | KCa1.1, KCa3.1 - Kv1.2, Kv1.3, Kv1.6 |
Iberiotoxin | 12IBX001 | KCa1.1 |
Leiurotoxin 1 (Scyllatoxin) | 10LEI001 | SK1, SK2, SK3 |
Tamapin | 10TAM001 | SK1, SK2, SK3 |
Kaliotoxin-1 | 08KTX002 | BK, Kv1.1, Kv1.2, Kv1.3 |
Kv channels | ||
ShK | 08SHK001 | Kv1.3, Kv1.1, Kv1.4, Kv1.6 |
TMR-ShK | SAT001 | Kv1.3, Kv1.1 |
Margatoxin | 08MAG001 | Kv1.3 |
(Dap22)-ShK | 13SHD001 | Kv1.3 |
ADWX-1 | 13ADW001 | Kv1.3 |
HsTx1 | 08NEU001 | Kv1.3, Kv1.2 |
Agitoxin-2 | 13AGI002 | Kv1.3, Kv1.1 |
Maurotoxin | 08MAR001 | Kv1.2, KCa3.1 |
Guangxitoxin 1E | 11GUA002 | Kv2.1, Kv2.2 |
Stromatoxin 1 NEW | SCT01 | Kv2.1, Kv2.2 |
Kaliotoxin-1 | 08KTX002 | BK, Kv1.1, Kv1.2, Kv1.3 |
Charybdotoxin | 11CHA001 | KCa1.1, KCa3.1 - Kv1.2, Kv1.3, Kv1.6 |
Phrixotoxin-2 | PHX002 | Kv4.2, Kv4.3 |
AmmTx3 NEW | AMX001 | A-type potassium channels |
Inwardly rectifying potassium channels | ||
TertiapinQ | 08TER001 | Kir1.1, Kir3.1/3.4, Kir3.1/3.2-KCa1.1 |
hERG/Kv11.1 | ||
BeKm-1 | 13BEK001 | ERG1 |
3. 作用于钙离子通道(Calcium channel)的毒素
Toxin name | Catalog # | Target |
High voltage-gated Ca2+ channels | ||
ω-agatoxin IVA | 11AGA001 | P/Qtype |
ω-Conotoxin MVIIC | 08CON002 | P/Qtype, N-type |
ω-Conotoxin MVIIA | 08CON001 | N-type |
ω-Conotoxin GVIA | 08CON003 | N-type |
ω-Conotoxin SO3 | 08CON013 | N-type |
Huwentoxin I | 07HWT001 | N-type |
ProTx-II | 07PTX002 | T-type, L-type |
Intermediate voltage-gated Ca2+ channels | ||
SNX482 | 08SNX002 | R-type |
Low voltage-gated Ca2+ channels | ||
ProTx-I | 12PTX001 | T-type |
ProTx-II | 07PTX002 | T-type, L-type |
Ryanodine receptors | ||
Maurocalcine | 07PAU001 | Ryr1 |
4. 作用于氯离子通道(Chloride channel)的毒素
Toxin name | Catalog # | Target |
Chlorotoxin | 08CHL001 | Blocker of small conductance Cl- channels |
GaTx1 | 13GTX001 | Selective blocker of CFTR channel |
GaTx2 | 10GTX002 | Selective blocker of ClC-2 channel |
5. 作用于乙酰胆碱受体(Acetylcholine receptor)的毒素
Toxin name | Catalog # | Target |
α-conotoxin PeIA | 13CON017 | α9α10, α3β2 subunits |
α-Conotoxin PrXA | 13CON016 | α1/β1/ε/δ, α1/β1/γ/δ subunits |
Waglerin-1 | 12WAG001 | MusclenAChR |
α-conotoxin MI | 08CON012 | α1/δsubunits |
α-conotoxin GI | 08CON005 | α/δsite |
α-conotoxin IMI | 08CON011 | α7 homomeric nAChR |
α-conotoxin GID | CON019 | Blocker of α3β2, α7 and α4β2 nAChRs |
6. 含N-甲基-D-天冬氨酸NR2B
(NMDA, NR2B containing N-methyl-D-aspartate)
Conantokin-G
选择性、特异性抑制含NR2B的NMDAR。Conantokin-G能剂量依赖性抑制Ca2+内流，抑制NMDA诱导的兴奋性中毒效应。研究表明，在小鼠皮层神经元，Conantokin-G阻滞NMDA引发的电流信号的IC50值为480 nM。
7. 作用于酸敏感离子通道(ASIC channel, Acid-Sensing Ion Channel)的毒素
Toxin name | Catalog # | Target |
APETx2 | 07APE002 | Selective blocker of ASIC3 |
Psalmotoxin1/PcTx1 | 13PCT001 | Selective blocker of ASIC1a |
Ugr9-1 | 13UGR001 | Blocker of ASIC3 |
8. 作用于瞬时受体电位(TRP channel, transient receptor potential)的毒素
Toxin name | Catalog # | Target |
GsMTx4 | 08GSM001 | TRPC, TRPA |
Vanillotoxin3 | 10VAN003 | Activator of TRPV1 |
ProTx-I | 12PTX001 | Antagonist of TRPA1 |
9. 作用于嘌呤能通道(Purinergic channel)的毒素
Purotoxin-1
选择性抑制P2X3受体。100 nM Purotoxin-1 (PT-1)选择性抑制P2X3受体通道，在大鼠DRG神经元上，使用膜片钳实验表明：PT-1对电压门控通道和TRPV1均无抑制效应。10 µM ATP和100 µM α,β Methylene-ATP浓度下Purotoxin-1对P2X3受体有选择性作用，在该ATP浓度下Purotoxin-1对P2X2和杂化二聚体P2X2/3并无激动作用。Purotoxin-1对疼痛的潜在治疗作用。
10. 作用于其它膜受体通道(Others)的毒素
Smartox Biotechnology还提供其他类型的膜受体抑制剂：
Toxin name | Catalog # | Target |
Morphiceptin | 011CAS001 | Agonist of µ-opoid receptors |
Lys-conopressin G | 11CON14 | Vasopressin-like peptide |
GsMTx4 | 08GSM001 | Mechano sensitive ion channels |
Obtustatin | 10OBT001 | Blocks the binding of α1β1 integrin to collagen IV |
Rho-Conotoxin TIA | CON022 | Blocks α1-adrenergic receptor |
公司简介
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)”。
总之，Smartox Biotechnolgy提供一系列高质量、具开创价值的多肽毒素。这些化合物在离子通道 研究中具有高的亲和性和选择性，是相应领域科学研究理想的生物毒素提供商和贴心的合作伙伴。
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