ProTx-III,newselectiveNav1.7blocker
ProTx-III (µ-TRTX-Tp1a;belongstoNaSpTxfamily1)hasbeenisolatedfromthevenomofthePeruviangreen-velvettarantulaThrixopelmapruriensattheUniversityofQueensland(Australia).ProTx-IIIhasbeendescribedtobeaselectiveinhibitorofNav1.7withanIC50valuearound2nM.ThesyntheticversionofTp1aproducedbySmartoxyieldssimilarresultsintermsofNav1.7inhibition(seeFigure1).QueenslandscientistshavedescribedthatProTx-III inducesnosignificantchangesinthevoltagedependenceofactivationorsteady-stateinactivationofNav1.7.ProTx-III alsoinhibitsNav1.1,Nav1.2 andNav1.6atnanomolarconcentrations anddoesnotaffectsCavchannelsandnicotinicacetylcholinereceptors. ProTx-IIIdemonstratesanalgesicpropertiesinvivowheninjectedintraplantaryinmicepriortreatmentwithOD1,anactivatorofNav1.7,whichinducesspontaneouspain.
Fig1:effectof5nMSmartoxProTx-IIIonhNav1.7current studiedbyelicitingvoltagestepsfrom-60to+40mVataholdingpotentialof-90mV.
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Description:
AAsequence: Asp-Cys2-Leu-Lys-Phe-Gly-Trp-Lys-Cys9-Asn-Pro-Arg-Asn-Asp-Lys-Cys16-Cys17-Ser-Gly-Leu-Lys-Cys22-Gly-Ser-Asn-His-Asn-Trp-Cys29-Lys-Leu-His-Ile-NH2
Disulfidebonds: Cys2-Cys17,Cys9-Cys22,Cys16-Cys29
Length(aa):33
Formula: C162H246N52O43S6
Appearance:Whitelyophilizedsolid
CASnumber:
MolecularWeight:3802.47Da
Source:Synthetic
Solubility:Waterorsalinebuffer,5mg/mLmaximum(recommendation)
Counterion:TFAsalts
Reference:
IdentificationandCharacterizationofProTx-III
Spidervenomsarearichsourceofionchannelmodulatorswiththerapeuticpotential.Giventheanalgesicpotentialofsubtype-selectiveinhibitorsofvoltage-gatedsodium(NaV)channels,wescreenedspidervenomsforinhibitorsofhumanNaV1.7(hNaV1.7)usingahigh-throughputfluorescentassay.Here,wedescribethediscoveryofanovelNaV1.7inhibitor,μ-TRTX-Tp1a(Tp1a),isolatedfromthevenomofthePeruviangreen-velvettarantulaThrixopelmapruriens.Recombinantandsyntheticformsofthis33-residuepeptidepreferentiallyinhibitedhNaV1.7>hNaV1.6>hNaV1.2>hNaV1.1>hNaV1.3channelsinfluorescentassays.NaV1.7inhibitionwasdiminished(IC5011.5nM)andtheassociationratedecreasedfortheC-terminalacidformofTp1acomparedwiththenativeamidatedform(IC502.1nM),suggestingthatthepeptideCterminuscontributestoitsinteractionwithhNaV1.7.Tp1ahadnoeffectonhumanvoltage-gatedcalciumchannelsornicotinicacetylcholinereceptorsat5μM.UnlikemostspidertoxinsthatmodulateNaVchannels,Tp1ainhibitedhNaV1.7withoutsignificantlyalteringthevoltagedependenceofactivationorinactivation.Tp1aprovedtobeanalgesicbyreversingspontaneouspaininducedinmicebyintraplantarinjectioninOD1,ascorpiontoxinthatpotentiateshNaV1.7.ThestructureofTp1aasdeterminedusingNMRspectroscopyrevealedaclassicinhibitorcystineknot(ICK)motif.ThemolecularsurfaceofTp1apresentsahydrophobicpatchsurroundedbypositivelychargedresidues,withsubtledifferencesfromotherICKspidertoxinsthatmightcontributetoitsdifferentpharmacologicalprofile.Tp1amayhelpguidethedevelopmentofmoreselectiveandpotenthNaV1.7inhibitorsfortreatmentofchronicpain.
FernandaC.,etal.(2015)IdentificationandCharacterizationofProTx-III[m-TRTX-Tp1a],aNewVoltage-GatedSodiumChannelInhibitorfromVenomoftheTarantulaThrixopelmapruriens.PMID: 25979003
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