Small-Molecule Quinolinol Inhibitor Identified Provides Protection against BoNTA in Mice 英文参考文献.docVIP

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Small-Molecule Quinolinol Inhibitor Identified Provides Protection against BoNTA in Mice 英文参考文献.doc

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Small-Molecule Quinolinol Inhibitor Identified Provides Protection against BoNTA in Mice 英文参考文献

Small-MoleculeQuinolinolInhibitorIdentifiedProvides ProtectionagainstBoNT/AinMice PadmaSingh,MangleshKumarSingh,DilipChaudhary,VinitaChauhan,PranayBharadwaj, ApurvaPandey,NishaUpadhyay,RamKumarDhaked* BiotechnologyDivision,DefenceResearchandDevelopmentEstablishment,Gwalior,MadhyaPradesh,India Abstract Botulinumneurotoxins(BoNTs),etiologicalagentsofthelifethreateningneuroparalyticdiseasebotulism,arethemosttoxic substancescurrentlyknown.Thepotentialfortheuseasbioweaponmakesthedevelopmentofsmall-moleculeinhibitor against these deadly toxins is a top priority. Currently, there are no approved pharmacological treatments for BoNT intoxication.Althoughaneffectivevaccine/immunotherapyisavailableforimmuno-prophylaxisbutthiscannotreversethe effects of toxin inside neurons. A small-molecule pharmacological intervention, especially one that would be effective againstthelightchain protease, wouldbe highlydesirable.Similarity searchwascarried outfrom ChemBridgeandNSC librariestothehit(7-(phenyl(8-quinolinylamino)methyl)-8-quinolinol;NSC84096)tomineitsanalogs.Severalhitsobtained werescreenedforinsilicoinhibitionusingAutoDock4.1and19newmoleculesselectedbasedonbindingenergyandKi. Amongthese,elevenquinolinolderivativespotentlyinhibitedinvitroendopeptidaseactivityofbotulinumneurotoxintype Alightchain(rBoNT/A-LC)onsynaptosomesisolatedfromratbrainwhichsimulatetheinvivosystem.Fiveoftheseinhibitor moleculesexhibitedIC50valuesrangingfrom3.0nMto10.0mM.NSC84087isthemostpotentinhibitorreportedsofar, foundtobeapromisingleadfortherapeuticdevelopment,asitexhibitsnotoxicity,andisabletoprotectanimalsfrompre andpostchallengeofbotulinumneurotoxintypeA(BoNT/A). Citation:SinghP,SinghMK,ChaudharyD,ChauhanV,BharadwajP,etal.(2012)Small-MoleculeQuinolinolInhibitorIdentifiedProvidesProtectionagainstBoNT/ AinMice.PLoSONE7(10):e47110.doi:10.1371/journal.pone.0047110 Editor:KamyarAfarinkia,UnivofBradford,UnitedKingdom ReceivedMay9,2012;AcceptedSeptember10,2012;PublishedOctober11,2012 Copyright: ? 2012 Si