JP2019531733A - ハイブリッド神経毒 - Google Patents
ハイブリッド神経毒 Download PDFInfo
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- JP2019531733A JP2019531733A JP2019517381A JP2019517381A JP2019531733A JP 2019531733 A JP2019531733 A JP 2019531733A JP 2019517381 A JP2019517381 A JP 2019517381A JP 2019517381 A JP2019517381 A JP 2019517381A JP 2019531733 A JP2019531733 A JP 2019531733A
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Abstract
Description
- 配列番号1のアミノ酸残基1乃至448、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、
- 配列番号2のアミノ酸残基1乃至441、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、
- 配列番号3のアミノ酸残基1乃至449、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、
- 配列番号4のアミノ酸残基1乃至442、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、
- 配列番号5のアミノ酸残基1から423、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、
- 配列番号6のアミノ酸残基1乃至439、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、
- 配列番号7のアミノ酸残基1乃至446、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、及び
- 配列番号8のアミノ酸残基1乃至456、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列。
- 配列番号1のアミノ酸残基449乃至872、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、
- 配列番号2のアミノ酸残基442乃至859、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、
- 配列番号3のアミノ酸残基450乃至867、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、
- 配列番号4のアミノ酸残基442乃至863、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、
- 配列番号5のアミノ酸残基423乃至846、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、
- 配列番号6のアミノ酸残基440乃至865、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、
- 配列番号7のアミノ酸残基447乃至864、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、及び
- 配列番号8のアミノ酸残基457乃至880、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列。
- 配列番号1のアミノ酸残基873乃至1094、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、
- 配列番号2のアミノ酸残基860乃至1081、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、
- 配列番号3のアミノ酸残基868乃至1095、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、
- 配列番号4のアミノ酸残基864から1082、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、
- 配列番号5のアミノ酸残基847乃至1069、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、
- 配列番号6のアミノ酸残基866乃至1087、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、
- 配列番号7のアミノ酸残基865乃至1089、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、又は
- 配列番号8のアミノ酸残基881乃至1111、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列。
- 配列番号1のアミノ酸残基1095乃至1296、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、
- 配列番号2のアミノ酸残基1082乃至1291、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、
- 配列番号3のアミノ酸残基1096乃至1291、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、
- 配列番号4のアミノ酸残基1083乃至1276、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、
- 配列番号5のアミノ酸残基1070乃至1252、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、
- 配列番号6のアミノ酸残基1088乃至1278、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、
- 配列番号7のアミノ酸残基1090から1297、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列、又は
- 配列番号8のアミノ酸残基1112乃至1315、又はこれに対して少なくとも70%、好ましくは少なくとも75%、80%、85%、90%、95%、又は99%の配列同一性を有するポリペプチド配列。
・ L - GBM
・ GBM - L
・ L - AS - GBM
・ GBM - AS - L
・ L - AS - GBM - TD
・ L - AS- TD - GBM
・ GBM - TD - AS -L
・ TD - GBM - AS -L
・ GBM - L - AS - TD
・ L - AS - GBM - TD - BD
・ L - AS - BD - TD - GBM
・ GBM - TD - BD - AS -L
・ BD - TD - GBM - AS -L
・ L - AS - GBM - HN
・ L - AS - HN - GBM
・ GBM - HN - AS -L
・ HN - GBM - AS -L
・ GBM - L - AS - HN
・ L - AS - GBM - HN - HCN
・ L - AS - GBM - HN - HCN - HCC
・ L - AS - HN - GBM
・ L - AS - HN - HCN - GBM
・ L - AS - HN - HCN - HCC- GBM
・ L - AS - GBM - リンカー - HN
・ L - AS - GBM - リンカー - HN - HCN
・ L - AS - GBM - リンカー - HN - HCN - HCC
・ L - AS - HN - リンカー - GBM
・ L - AS - HN - HCN - リンカー - GBM
・ L - AS - HN - HCN - HCC - リンカー - GBM
・ GBM -L - AS -HN -HCN -HCC
・ L - AS - リンカー - GBM - HN
・ L - AS - リンカー - GBM - HN - HCN
・ L - AS - リンカー - GBM - HN - HCN - HCC
・ L - AS - リンカー - GBM - リンカー - HN
・ L - AS - リンカー - GBM - リンカー - HN - HCN
・ L - AS - リンカー - GBM - リンカー - HN - HCN - HCC
・ 配列番号1 - BoNT/A1 - UniProtKB 受入番号 P10845 (Clostridium botulinum)
MPFVNKQFNYKDPVNGVDIAYIKIPNAGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLNPPPEAKQVPVSYYDSTYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGGSTIDTELKVIDTNCINVIQPDGSYRSEELNLVIIGPSADIIQFECKSFGHEVLNLTRNGYGSTQYIRFSPDFTFGFEESLEVDTNPLLGAGKFATDPAVTLAHELIHAGHRLYGIAINPNRVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLYYYNKFKDIASTLNKAKSIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKVLNRKTYLNFDKAVFKINIVPKVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFTKLKNFTGLFEFYKLLCVRGIITSKTKSLDKGYNKALNDLCIKVNNWDLFFSPSEDNFTNDLNKGEEITSDTNIEAAEENISLDLIQQYYLTFNFDNEPENISIENLSSDIIGQLELMPNIERFPNGKKYELDKYTMFHYLRAQEFEHGKSRIALTNSVNEALLNPSRVYTFFSSDYVKKVNKATEAAMFLGWVEQLVYDFTDETSEVSTTDKIADITIIIPYIGPALNIGNMLYKDDFVGALIFSGAVILLEFIPEIAIPVLGTFALVSYIANKVLTVQTIDNALSKRNEKWDEVYKYIVTNWLAKVNTQIDLIRKKMKEALENQAEATKAIINYQYNQYTEEEKNNINFNIDDLSSKLNESINKAMININKFLNQCSVSYLMNSMIPYGVKRLEDFDASLKDALLKYIYDNRGTLIGQVDRLKDKVNNTLSTDIPFQLSKYVDNQRLLSTFTEYIKNIINTSILNLRYESNHLIDLSRYASKINIGSKVNFDPIDKNQIQLFNLESSKIEVILKNAIVYNSMYENFSTSFWIRIPKYFNSISLNNEYTIINCMENNSGWKVSLNYGEIIWTLQDTQEIKQRVVFKYSQMINISDYINRWIFVTITNNRLNNSKIYINGRLIDQKPISNLGNIHASNNIMFKLDGCRDTHRYIWIKYFNLFDKELNEKEIKDLYDNQSNSGILKDFWGDYLQYDKPYYMLNLYDPNKYVDVNNVGIRGYMYLKGPRGSVMTTNIYLNSSLYRGTKFIIKKYASGNKDNIVRNNDRVYINVVVKNKEYRLATNASQAGVEKILSALEIPDVGNLSQVVVMKSKNDQGITNKCKMNLQDNNGNDIGFIGFHQFNNIAKLVASNWYNRQIERSSRTLGCSWEFIPVDDGWGERPL
・ 配列番号2 - BoNT/B1 - UniProtKB 受入番号 P10844 (Clostridium botulinum)
MPVTINNFNYNDPIDNNNIIMMEPPFARGTGRYYKAFKITDRIWIIPERYTFGYKPEDFNKSSGIFNRDVCEYYDPDYLNTNDKKNIFLQTMIKLFNRIKSKPLGEKLLEMIINGIPYLGDRRVPLEEFNTNIASVTVNKLISNPGEVERKKGIFANLIIFGPGPVLNENETIDIGIQNHFASREGFGGIMQMKFCPEYVSVFNNVQENKGASIFNRRGYFSDPALILMHELIHVLHGLYGIKVDDLPIVPNEKKFFMQSTDAIQAEELYTFGGQDPSIITPSTDKSIYDKVLQNFRGIVDRLNKVLVCISDPNININIYKNKFKDKYKFVEDSEGKYSIDVESFDKLYKSLMFGFTETNIAENYKIKTRASYFSDSLPPVKIKNLLDNEIYTIEEGFNISDKDMEKEYRGQNKAINKQAYEEISKEHLAVYKIQMCKSVKAPGICIDVDNEDLFFIADKNSFSDDLSKNERIEYNTQSNYIENDFPINELILDTDLISKIELPSENTESLTDFNVDVPVYEKQPAIKKIFTDENTIFQYLYSQTFPLDIRDISLTSSFDDALLFSNKVYSFFSMDYIKTANKVVEAGLFAGWVKQIVNDFVIEANKSNTMDKIADISLIVPYIGLALNVGNETAKGNFENAFEIAGASILLEFIPELLIPVVGAFLLESYIDNKNKIIKTIDNALTKRNEKWSDMYGLIVAQWLSTVNTQFYTIKEGMYKALNYQAQALEEIIKYRYNIYSEKEKSNINIDFNDINSKLNEGINQAIDNINNFINGCSVSYLMKKMIPLAVEKLLDFDNTLKKNLLNYIDENKLYLIGSAEYEKSKVNKYLKTIMPFDLSIYTNDTILIEMFNKYNSEILNNIILNLRYKDNNLIDLSGYGAKVEVYDGVELNDKNQFKLTSSANSKIRVTQNQNIIFNSVFLDFSVSFWIRIPKYKNDGIQNYIHNEYTIINCMKNNSGWKISIRGNRIIWTLIDINGKTKSVFFEYNIREDISEYINRWFFVTITNNLNNAKIYINGKLESNTDIKDIREVIANGEIIFKLDGDIDRTQFIWMKYFSIFNTELSQSNIEERYKIQSYSEYLKDFWGNPLMYNKEYYMFNAGNKNSYIKLKKDSPVGEILTRSKYNQNSKYINYRDLYIGEKFIIRRKSNSQSINDDIVRKEDYIYLDFFNLNQEWRVYTYKYFKKEEEKLFLAPISDSDEFYNTIQIKEYDEQPTYSCQLLFKKDEESTDEIGLIGIHRFYESGIVFEEYKDYFCISKWYLKEVKRKPYNLKLGCNWQFIPKDEGWTE
・ 配列番号3 - BoNT/C1 - UniProtKB 受入番号 P18640 (Clostridium botulinum)
MPITINNFNYSDPVDNKNILYLDTHLNTLANEPEKAFRITGNIWVIPDRFSRNSNPNLNKPPRVTSPKSGYYDPNYLSTDSDKDPFLKEIIKLFKRINSREIGEELIYRLSTDIPFPGNNNTPINTFDFDVDFNSVDVKTRQGNNWVKTGSINPSVIITGPRENIIDPETSTFKLTNNTFAAQEGFGALSIISISPRFMLTYSNATNDVGEGRFSKSEFCMDPILILMHELNHAMHNLYGIAIPNDQTISSVTSNIFYSQYNVKLEYAEIYAFGGPTIDLIPKSARKYFEEKALDYYRSIAKRLNSITTANPSSFNKYIGEYKQKLIRKYRFVVESSGEVTVNRNKFVELYNELTQIFTEFNYAKIYNVQNRKIYLSNVYTPVTANILDDNVYDIQNGFNIPKSNLNVLFMGQNLSRNPALRKVNPENMLYLFTKFCHKAIDGRSLYNKTLDCRELLVKNTDLPFIGDISDVKTDIFLRKDINEETEVIYYPDNVSVDQVILSKNTSEHGQLDLLYPSIDSESEILPGENQVFYDNRTQNVDYLNSYYYLESQKLSDNVEDFTFTRSIEEALDNSAKVYTYFPTLANKVNAGVQGGLFLMWANDVVEDFTTNILRKDTLDKISDVSAIIPYIGPALNISNSVRRGNFTEAFAVTGVTILLEAFPEFTIPALGAFVIYSKVQERNEIIKTIDNCLEQRIKRWKDSYEWMMGTWLSRIITQFNNISYQMYDSLNYQAGAIKAKIDLEYKKYSGSDKENIKSQVENLKNSLDVKISEAMNNINKFIRECSVTYLFKNMLPKVIDELNEFDRNTKAKLINLIDSHNIILVGEVDKLKAKVNNSFQNTIPFNIFSYTNNSLLKDIINEYFNNINDSKILSLQNRKNTLVDTSGYNAEVSEEGDVQLNPIFPFDFKLGSSGEDRGKVIVTQNENIVYNSMYESFSISFWIRINKWVSNLPGYTIIDSVKNNSGWSIGIISNFLVFTLKQNEDSEQSINFSYDISNNAPGYNKWFFVTVTNNMMGNMKIYINGKLIDTIKVKELTGINFSKTITFEINKIPDTGLITSDSDNINMWIRDFYIFAKELDGKDINILFNSLQYTNVVKDYWGNDLRYNKEYYMVNIDYLNRYMYANSRQIVFNTRRNNNDFNEGYKIIIKRIRGNTNDTRVRGGDILYFDMTINNKAYNLFMKNETMYADNHSTEDIYAIGLREQTKDINDNIIFQIQPMNNTYYYASQIFKSNFNGENISGICSIGTYRFRLGGDWYRHNYLVPTVKQGNYASLLESTSTHWGFVPVSE
・ 配列番号4 - BoNT/D - UniProtKB 受入番号 P19321 (Clostridium botulinum)
MTWPVKDFNYSDPVNDNDILYLRIPQNKLITTPVKAFMITQNIWVIPERFSSDTNPSLSKPPRPTSKYQSYYDPSYLSTDEQKDTFLKGIIKLFKRINERDIGKKLINYLVVGSPFMGDSSTPEDTFDFTRHTTNIAVEKFENGSWKVTNIITPSVLIFGPLPNILDYTASLTLQGQQSNPSFEGFGTLSILKVAPEFLLTFSDVTSNQSSAVLGKSIFCMDPVIALMHELTHSLHQLYGINIPSDKRIRPQVSEGFFSQDGPNVQFEELYTFGGLDVEIIPQIERSQLREKALGHYKDIAKRLNNINKTIPSSWISNIDKYKKIFSEKYNFDKDNTGNFVVNIDKFNSLYSDLTNVMSEVVYSSQYNVKNRTHYFSRHYLPVFANILDDNIYTIRDGFNLTNKGFNIENSGQNIERNPALQKLSSESVVDLFTKVCLRLTKNSRDDSTCIKVKNNRLPYVADKDSISQEIFENKIITDETNVQNYSDKFSLDESILDGQVPINPEIVDPLLPNVNMEPLNLPGEEIVFYDDITKYVDYLNSYYYLESQKLSNNVENITLTTSVEEALGYSNKIYTFLPSLAEKVNKGVQAGLFLNWANEVVEDFTTNIMKKDTLDKISDVSVIIPYIGPALNIGNSALRGNFNQAFATAGVAFLLEGFPEFTIPALGVFTFYSSIQEREKIIKTIENCLEQRVKRWKDSYQWMVSNWLSRITTQFNHINYQMYDSLSYQADAIKAKIDLEYKKYSGSDKENIKSQVENLKNSLDVKISEAMNNINKFIRECSVTYLFKNMLPKVIDELNKFDLRTKTELINLIDSHNIILVGEVDRLKAKVNESFENTMPFNIFSYTNNSLLKDIINEYFNSINDSKILSLQNKKNALVDTSGYNAEVRVGDNVQLNTIYTNDFKLSSSGDKIIVNLNNNILYSAIYENSSVSFWIKISKDLTNSHNEYTIINSIEQNSGWKLCIRNGNIEWILQDVNRKYKSLIFDYSESLSHTGYTNKWFFVTITNNIMGYMKLYINGELKQSQKIEDLDEVKLDKTIVFGIDENIDENQMLWIRDFNIFSKELSNEDINIVYEGQILRNVIKDYWGNPLKFDTEYYIINDNYIDRYIAPESNVLVLVQYPDRSKLYTGNPITIKSVSDKNPYSRILNGDNIILHMLYNSRKYMIIRDTDTIYATQGGECSQNCVYALKLQSNLGNYGIGIFSIKNIVSKNKYCSQIFSSFRENTMLLADIYKPWRFSFKNAYTPVAVTNYETKLLSTSSFWKFISRDPGWVE
・ 配列番号5 - BoNT/E - 受入番号 WP_003372387 (Clostridium botulinum)
MPKINSFNYNDPVNDRTILYIKPGGCQEFYKSFNIMKNIWIIPERNVIGTTPQDFHPPTSLKNGDSSYYDPNYLQSDEEKDRFLKIVTKIFNRINNNLSGGILLEELSKANPYLGNDNTPDNQFHIGDASAVEIKFSNGSQDILLPNVIIMGAEPDLFETNSSNISLRNNYMPSNHGFGSIAIVTFSPEYSFRFNDNSMNEFIQDPALTLMHELIHSLHGLYGAKGITTKYTITQKQNPLITNIRGTNIEEFLTFGGTDLNIITSAQSNDIYTNLLADYKKIASKLSKVQVSNPLLNPYKDVFEAKYGLDKDASGIYSVNINKFNDIFKKLYSFTEFDLATKFQVKCRQTYIGQYKYFKLSNLLNDSIYNISEGYNINNLKVNFRGQNANLNPRIITPITGRGLVKKIIRFCKNIVSVKGIRKSICIEINNGELFFVASENSYNDDNINTPKEIDDTVTSNNNYENDLDQVILNFNSESAPGLSDEKLNLTIQNDAYIPKYDSNGTSDIEQHDVNELNVFFYLDAQKVPEGENNVNLTSSIDTALLEQPKIYTFFSSEFINNVNKPVQAALFVSWIQQVLVDFTTEANQKSTVDKIADISIVVPYIGLALNIGNEAQKGNFKDALELLGAGILLEFEPELLIPTILVFTIKSFLGSSDNKNKVIKAINNALKERDEKWKEVYSFIVSNWMTKINTQFNKRKEQMYQALQNQVNAIKTIIESKYNSYTLEEKNELTNKYDIKQIENELNQKVSIAMNNIDRFLTESSISYLMKLINEVKINKLREYDENVKTYLLNYIIQHGSILGESQQELNSMVTDTLNNSIPFKLSSYTDDKILISYFNKFFKRIKSSSVLNMRYKNDKYVDTSGYDSNININGDVYKYPTNKNQFGIYNDKLSEVNISQNDYIIYDNKYKNFSISFWVRIPNYDNKIVNVNNEYTIINCMRDNNSGWKVSLNHNEIIWTLQDNAGINQKLAFNYGNANGISDYINKWIFVTITNDRLGDSKLYINGNLIDQKSILNLGNIHVSDNILFKIVNCSYTRYIGIRYFNIFDKELDETEIQTLYSNEPNTNILKDFWGNYLLYDKEYYLLNVLKPNNFIDRRKDSTLSINNIRSTILLANRLYSGIKVKIQRVNNSSTNDNLVRKNDQVYINFVASKTHLFPLYADTATTNKEKTIKISSSGNRFNQVVVMNSVGNNCTMNFKNNNGNNIGLLGFKADTVVASTWYYTHMRDHTNSNGCFWNFISEEHGWQEK
・ 配列番号6 - BoNT/F - UniProtKB 受入番号 YP_001390123 (Clostridium botulinum)
MPVVINSFNYNDPVNDDTILYMQIPYEEKSKKYYKAFEIMRNVWIIPERNTIGTDPSDFDPPASLENGSSAYYDPNYLTTDAEKDRYLKTTIKLFKRINSNPAGEVLLQEISYAKPYLGNEHTPINEFHPVTRTTSVNIKSSTNVKSSIILNLLVLGAGPDIFENSSYPVRKLMDSGGVYDPSNDGFGSINIVTFSPEYEYTFNDISGGYNSSTESFIADPAISLAHELIHALHGLYGARGVTYKETIKVKQAPLMIAEKPIRLEEFLTFGGQDLNIITSAMKEKIYNNLLANYEKIATRLSRVNSAPPEYDINEYKDYFQWKYGLDKNADGSYTVNENKFNEIYKKLYSFTEIDLANKFKVKCRNTYFIKYGFLKVPNLLDDDIYTVSEGFNIGNLAVNNRGQNIKLNPKIIDSIPDKGLVEKIVKFCKSVIPRKGTKAPPRLCIRVNNRELFFVASESSYNENDINTPKEIDDTTNLNNNYRNNLDEVILDYNSETIPQISNQTLNTLVQDDSYVPRYDSNGTSEIEEHNVVDLNVFFYLHAQKVPEGETNISLTSSIDTALSEESQVYTFFSSEFINTINKPVHAALFISWINQVIRDFTTEATQKSTFDKIADISLVVPYVGLALNIGNEVQKENFKEAFELLGAGILLEFVPELLIPTILVFTIKSFIGSSENKNKIIKAINNSLMERETKWKEIYSWIVSNWLTRINTQFNKRKEQMYQALQNQVDAIKTVIEYKYNNYTSDERNRLESEYNINNIREELNKKVSLAMENIERFITESSIFYLMKLINEAKVSKLREYDEGVKEYLLDYISEHRSILGNSVQELNDLVTSTLNNSIPFELSSYTNDKILILYFNKLYKKIKDNSILDMRYENNKFIDISGYGSNISINGDVYIYSTNRNQFGIYSSKPSEVNIAQNNDIIYNGRYQNFSISFWVRIPKYFNKVNLNNEYTIIDCIRNNNSGWKISLNYNKIIWTLQDTAGNNQKLVFNYTQMISISDYINKWIFVTITNNRLGNSRIYINGNLIDEKSISNLGDIHVSDNILFKIVGCNDTRYVGIRYFKVFDTELGKTEIETLYSDEPDPSILKDFWGNYLLYNKRYYLLNLLRTDKSITQNSNFLNINQQRGVYQKPNIFSNTRLYTGVEVIIRKNGSTDISNTDNFVRKNDLAYINVVDRDVEYRLYADISIAKPEKIIKLIRTSNSNNSLGQIIVMDSIGNNCTMNFQNNNGGNIGLLGFHSNNLVASSWYYNNIRKNTSSNGCFWSFISKEHGWQEN
・ 配列番号7 - BoNT/G - UniProtKB 受入番号 WP_039635782 (Clostridium botulinum)
MPVNIKNFNYNDPINNDDIIMMEPFNDPGPGTYYKAFRIIDRIWIVPERFTYGFQPDQFNASTGVFSKDVYEYYDPTYLKTDAEKDKFLKTMIKLFNRINSKPSGQRLLDMIVDAIPYLGNASTPPDKFAANVANVSINKKIIQPGAEDQIKGLMTNLIIFGPGPVLSDNFTDSMIMNGHSPISEGFGARMMIRFCPSCLNVFNNVQENKDTSIFSRRAYFADPALTLMHELIHVLHGLYGIKISNLPITPNTKEFFMQHSDPVQAEELYTFGGHDPSVISPSTDMNIYNKALQNFQDIANRLNIVSSAQGSGIDISLYKQIYKNKYDFVEDPNGKYSVDKDKFDKLYKALMFGFTETNLAGEYGIKTRYSYFSEYLPPIKTEKLLDNTIYTQNEGFNIASKNLKTEFNGQNKAVNKEAYEEISLEHLVIYRIAMCKPVMYKNTGKSEQCIIVNNEDLFFIANKDSFSKDLAKAETIAYNTQNNTIENNFSIDQLILDNDLSSGIDLPNENTEPFTNFDDIDIPVYIKQSALKKIFVDGDSLFEYLHAQTFPSNIENLQLTNSLNDALRNNNKVYTFFSTNLVEKANTVVGASLFVNWVKGVIDDFTSESTQKSTIDKVSDVSIIIPYIGPALNVGNETAKENFKNAFEIGGAAILMEFIPELIVPIVGFFTLESYVGNKGHIIMTISNALKKRDQKWTDMYGLIVSQWLSTVNTQFYTIKERMYNALNNQSQAIEKIIEDQYNRYSEEDKMNINIDFNDIDFKLNQSINLAINNIDDFINQCSISYLMNRMIPLAVKKLKDFDDNLKRDLLEYIDTNELYLLDEVNILKSKVNRHLKDSIPFDLSLYTKDTILIQVFNNYISNISSNAILSLSYRGGRLIDSSGYGATMNVGSDVIFNDIGNGQFKLNNSENSNITAHQSKFVVYDSMFDNFSINFWVRTPKYNNNDIQTYLQNEYTIISCIKNDSGWKVSIKGNRIIWTLIDVNAKSKSIFFEYSIKDNISDYINKWFSITITNDRLGNANIYINGSLKKSEKILNLDRINSSNDIDFKLINCTDTTKFVWIKDFNIFGRELNATEVSSLYWIQSSTNTLKDFWGNPLRYDTQYYLFNQGMQNIYIKYFSKASMGETAPRTNFNNAAINYQNLYLGLRFIIKKASNSRNINNDNIVREGDYIYLNIDNISDESYRVYVLVNSKEIQTQLFLAPINDDPTFYDVLQIKKYYEKTTYNCQILCEKDTKTFGLFGIGKFVKDYGYVWDTYDNYFCISQWYLRRISENINKLRLGCNWQFIPVDEGWTE
・ 配列番号8 - TeNT - UniProtKB 受入番号 P04958 (Clostridium tetani)
MPITINNFRYSDPVNNDTIIMMEPPYCKGLDIYYKAFKITDRIWIVPERYEFGTKPEDFNPPSSLIEGASEYYDPNYLRTDSDKDRFLQTMVKLFNRIKNNVAGEALLDKIINAIPYLGNSYSLLDKFDTNSNSVSFNLLEQDPSGATTKSAMLTNLIIFGPGPVLNKNEVRGIVLRVDNKNYFPCRDGFGSIMQMAFCPEYVPTFDNVIENITSLTIGKSKYFQDPALLLMHELIHVLHGLYGMQVSSHEIIPSKQEIYMQHTYPISAEELFTFGGQDANLISIDIKNDLYEKTLNDYKAIANKLSQVTSCNDPNIDIDSYKQIYQQKYQFDKDSNGQYIVNEDKFQILYNSIMYGFTEIELGKKFNIKTRLSYFSMNHDPVKIPNLLDDTIYNDTEGFNIESKDLKSEYKGQNMRVNTNAFRNVDGSGLVSKLIGLCKKIIPPTNIRENLYNRTASLTDLGGELCIKIKNEDLTFIAEKNSFSEEPFQDEIVSYNTKNKPLNFNYSLDKIIVDYNLQSKITLPNDRTTPVTKGIPYAPEYKSNAASTIEIHNIDDNTIYQYLYAQKSPTTLQRITMTNSVDDALINSTKIYSYFPSVISKVNQGAQGILFLQWVRDIIDDFTNESSQKTTIDKISDVSTIVPYIGPALNIVKQGYEGNFIGALETTGVVLLLEYIPEITLPVIAALSIAESSTQKEKIIKTIDNFLEKRYEKWIEVYKLVKAKWLGTVNTQFQKRSYQMYRSLEYQVDAIKKIIDYEYKIYSGPDKEQIADEINNLKNKLEEKANKAMININIFMRESSRSFLVNQMINEAKKQLLEFDTQSKNILMQYIKANSKFIGITELKKLESKINKVFSTPIPFSYSKNLDCWVDNEEDIDVILKKSTILNLDINNDIISDISGFNSSVITYPDAQLVPGINGKAIHLVNNESSEVIVHKAMDIEYNDMFNNFTVSFWLRVPKVSASHLEQYGTNEYSIISSMKKHSLSIGSGWSVSLKGNNLIWTLKDSAGEVRQITFRDLPDKFNAYLANKWVFITITNDRLSSANLYINGVLMGSAEITGLGAIREDNNITLKLDRCNNNNQYVSIDKFRIFCKALNPKEIEKLYTSYLSITFLRDFWGNPLRYDTEYYLIPVASSSKDVQLKNITDYMYLTNAPSYTNGKLNIYYRRLYNGLKFIIKRYTPNNEIDSFVKSGDFIKLYVSYNNNEHIVGYPKDGNAFNNLDRILRVGYNAPGIPLYKKMEAVKLRDLKTYSVQLKLYDDKNASLGLVGTHNGQIGNDPNRDILIASNWYFNHLKDKILGCDWYFVPTDEGWTND
・ 配列番号9 - コレラ毒素Bサブユニット (Vibrio cholera)
MIKLKFGVFFTVLLSSAYAHGTPQNITDLCAEYHNTQIYTLNDKIFSYTESLAGKREMAIITFKNGAIFQVEVPGSQHIDSQKKAIERMKDTLRIAYLTEAKVEKLCVWNNKTPHAIAAISMAN
・ 配列番号10 - コレラ毒素Aサブユニット (Vibrio cholera)
MVKIIFVFFIFLSSFSYANDDKLYRADSRPPDEIKQSGGLMPRGQSEYFDRGTQMNINLYDHARGTQTGFVRHDDGYVSTSISLRSAHLVGQTILSGHSTYYIYVIATAPNMFNVNDVLGAYSPHPDEQEVSALGGIPYSQIYGWYRVHFGVLDEQLHRNRGYRDRYYSNLDIAPAADGYGLAGFPPEHRAWREEPWIHHAPPGCGNAPRSSMSNTCDEKTQSLGVKFLDEYQSKVKRQIFSGYQSDIDTHNRIKDEL
・ 配列番号11 - BoNT/A1(0)-CtxBCP (人工配列)
MGSMEFVNKQFNYKDPVNGVDIAYIKIPNAGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLNPPPEAKQVPVSYYDSTYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGGSTIDTELKVIDTNCINVIQPDGSYRSEELNLVIIGPSADIIQFECKSFGHEVLNLTRNGYGSTQYIRFSPDFTFGFEESLEVDTNPLLGAGKFATDPAVTLAHQLIYAGHRLYGIAINPNRVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLYYYNKFKDIASTLNKAKSIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKVLNRKTYLNFDKAVFKINIVPKVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFTKLKNFTGLFEFYKLLCVDGIITSKTKSDDDDKTPQNITDLCAEYHNTQIHTLNDKIFSYTESLAGKREMAIITFKNGATFQVEVPGSQHIDSQKKAIERMKDTLRIAYLTEAKVEKLCVWNNKTPHAIAAISMANSGGGGSGGGGSGGGGSPRGSALNLQCIKVNNWDLFFSPSEDNFTNDLNKGEEITSDTNIEAAEENISLDLIQQYYLTFNFDNEPENISIENLSSDIIGQLELMPNIERFPNGKKYELDKYTMFHYLRAQEFEHGKSRIALTNSVNEALLNPSRVYTFFSSDYVKKVNKATEAAMFLGWVEQLVYDFTDETSEVSTTDKIADITIIIPYIGPALNIGNMLYKDDFVGALIFSGAVILLEFIPEIAIPVLGTFALVSYIANKVLTVQTIDNALSKRNEKWDEVYKYIVTNWLAKVNTQIDLIRKKMKEALENQAEATKAIINYQYNQYTEEEKNNINFNIDDLSSKLNESINKAMININKFLNQCSVSYLMNSMIPYGVKRLEDFDASLKDALLKYIYDNRGTLIGQVDRLKDKVNNTLSTDIPFQLSKYVDNQRLLSTFTEYIKNIINTSILNLRYESNHLIDLSRYASKINIGSKVNFDPIDKNQIQLFNLESSKIEVILKNAIVYNSMYENFSTSFWIRIPKYFNSISLNNEYTIINCMENNSGWKVSLNYGEIIWTLQDTQEIKQRVVFKYSQMINISDYINRWIFVTITNNRLNNSKIYINGRLIDQKPISNLGNIHASNNIMFKLDGCRDTHRYIWIKYFNLFDKELNEKEIKDLYDNQSNSGILKDFWGDYLQYDKPYYMLNLYDPNKYVDVNNVGIRGYMYLKGPRGSVMTTNIYLNSSLYRGTKFIIKKYASGNKDNIVRNNDRVYINVVVKNKEYRLATNASQAGVEKILSALEIPDVGNLSQVVVMKSKNDQGITNKCKMNLQDNNGNDIGFIGFHQFNNIAKLVASNWYNRQIERSSRTLGCSWEFIPVDDGWGERPLRKSFHHHHHH
・BoNT/A1(0)は、予想通り、GM1結合に対してCtx-B(Ctx-B-HRP)と競合しなかった。
・遊離Ctx-Bは、予想通り、Ctx-B-HRPと競合し、pEC50は、0.2μg/mlとなった。
・BoNT/A1(0)-CtxBCPは、遊離Ctx-B(49μg/ml)の約100分の1のpEC50を示すCtx-B-HRPと競合することができた。
BenchMark ladder: ベンチマークラダー
Total lysate: 全溶解物
Load: ロード
Flow through/wash: フロースルー/ウォッシュ
[図3]
BenchMark ladder: ベンチマークラダー
Flow through: フロースルー
Wash: ウォッシュ
[図4]
BenchMark ladder: ベンチマークラダー
Non-activated control: 非活性化対照
Final product: 最終産物
[図5A及び5B]
Total lysate: 全溶解物
Capture load: 捕獲ロード
Non-activated control: 非活性化対照
Final product: 最終産物
[図6]
GM1 binding assay: GM1結合アッセイ
ELISA Competition format: ELISA競合フォーマット
Absorbance: 吸光度
Basal: 基底
Competitor: 競合物
free Ctx-B: 遊離Ctx-B
Competition of 40μg/ml CtxB-HRP: 40μg/ml CtxB-HRPの競合
data is mean ± s.e.mean of triplicate wells: データは3連ウェルの平均値±平均値の標準誤差
Claims (20)
- クロストリジウム軽鎖(L)及び選択的ガングリオシド結合部分を含み、前記選択的ガングリオシド結合部分は、クロストリジウムHCC又はHCドメインではない、ハイブリッド神経毒。
- 前記ハイブリッド神経毒は、更に転位置部分を含む、請求項1記載のハイブリッド神経毒。
- 前記転位置部分は、クロストリジウムHNドメイン、コレラ毒素A2サブユニット(CtxA2)、及び細胞透過性ペプチドからなる群から選択される、請求項2記載のハイブリッド神経毒。
- 前記転位置部分は、クロストリジウムHNドメインであり、前記ハイブリッド神経毒は、軽鎖とクロストリジウムHNドメインとの間に活性化部位を含む、請求項2又は3記載のハイブリッド神経毒。
- 前記ハイブリッド神経毒は、更にクロストリジウムHCN及び/又はHCCドメインを含む、請求項1乃至4の何れかに記載のハイブリッド神経毒。
- 前記選択的ガングリオシド結合部分は、GM1a又はGM1b等のGM1、GM2、NeuAc GM3又はNeuGc GM3等のGM3、GM4、GD1a、GalNAc-GD1a、GT1a、GT1b、GQ1b、GD2、GD3、及びその任意の組み合わせからなる群から選択される1つ以上のガングリオシドに結合する、請求項1乃至5の何れかに記載のハイブリッド神経毒。
- 前記選択的ガングリオシド結合部分は、GM1に結合し、前記選択的ガングリオシド結合部分は、1つ以上のコレラ毒素Bサブユニット(CtxB)又は大腸菌易熱性エンテロトキシン(LT)を含む、請求項6記載のハイブリッド神経毒。
- 前記選択的ガングリオシド結合部分は、1つ以上のコレラ毒素Bサブユニット(CtxB)を含み、前記軽鎖は、前記1つ以上のコレラ毒素Bサブユニット(CtxB)に共有結合している、請求項7記載のハイブリッド神経毒。
- 前記選択的ガングリオシド結合部分は、1つ以上のコレラ毒素Bサブユニット(CtxB)を含み、前記ハイブリッド神経毒は、コレラ毒素A2サブユニット(CtxA2)を含み、前記CtxA2は、前記クロストリジウム軽鎖に共有結合しており、前記CtxBは、前記クロストリジウム軽鎖と非共有結合を形成する、請求項7記載のハイブリッド神経毒。
- 前記クロストリジウム軽鎖は、BoNT A型、B型、C1型、D型、E型、F型、若しくはG型又はTeNTに由来する、請求項1乃至9の何れかに記載のハイブリッド神経毒。
- 請求項1乃至10の何れかに記載のハイブリッド神経毒をコードするヌクレオチド配列。
- 請求項11記載のヌクレオチド配列を含むベクター。
- 請求項11記載のヌクレオチド配列又は請求項12記載のベクターを含む細胞。
- 請求項1乃至10の何れかに記載のハイブリッド神経毒を含む医薬組成物。
- 治療に使用する請求項1乃至10の何れかに記載のハイブリッド神経毒又は請求項14記載の医薬組成物。
- 前記選択的ガングリオシド結合部分は、GM1a、GM1b、GD1a、及びGalNAc-GD1aから選択された1つ以上のガングリオシドに結合する、望まれないニューロン活性に関連する四肢障害の治療に使用する請求項1乃至10の何れかに記載のハイブリッド神経毒又は請求項14記載の医薬組成物。
- 前記選択的ガングリオシド結合部分は、GT1a及びGQ1bから選択される1つ以上のガングリオシドに結合する、望まれないニューロン活性に関連する頭頸部障害の治療に使用する請求項1乃至10の何れかに記載のハイブリッド神経毒又は請求項14記載の医薬組成物。
- 前記選択的ガングリオシド結合部分は、ガングリオシド部分GM1に結合する、流涎症の治療に使用する請求項1乃至10の何れかに記載のハイブリッド神経毒又は請求項14記載の医薬組成物。
- 前記選択的ガングリオシド結合部分は、NeuAc GM3、NeuGc GM3、GM2、GM1、GD3、及びGD2から選択される1つ以上のガングリオシドに結合する、癌の治療に使用する請求項1乃至10の何れかに記載のハイブリッド神経毒又は請求項14記載の医薬組成物。
- 審美的状態を処置する請求項1乃至10の何れかに記載のハイブリッド神経毒又は請求項14記載の医薬組成物の非治療的使用。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2011045377A (ja) * | 2002-09-12 | 2011-03-10 | Health Protection Agency | 組換え毒素フラグメント |
JP2012519724A (ja) * | 2009-03-09 | 2012-08-30 | ヘンルイ ウイルリアム | シグナルペプチドを担体として有する細菌毒素とのハプテン‐担体抱合体及び免疫原性組成物としてのその使用 |
JP2013139454A (ja) * | 2004-09-06 | 2013-07-18 | Toxogen Gmbh | 神経細胞に化合物を導入するために用いられる輸送タンパク質 |
Family Cites Families (79)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE69435254D1 (de) | 1993-06-10 | 2009-12-31 | Allergan Inc | Behandlung von neuromusculaeren Störungen und Zuständen mit verschiedenen botulism Serotypen |
US5437291A (en) | 1993-08-26 | 1995-08-01 | Univ Johns Hopkins | Method for treating gastrointestinal muscle disorders and other smooth muscle dysfunction |
US6974578B1 (en) | 1993-12-28 | 2005-12-13 | Allergan, Inc. | Method for treating secretions and glands using botulinum toxin |
US20040126396A1 (en) | 1993-12-28 | 2004-07-01 | Allergan, Inc. | Botulinum toxin treatment for strabismus |
US5670484A (en) | 1994-05-09 | 1997-09-23 | Binder; William J. | Method for treatment of skin lesions associated with cutaneous cell-proliferative disorders |
US5714469A (en) | 1994-09-01 | 1998-02-03 | Smithkline Beecham Corporation | Method of treating sepsis |
GB9508204D0 (en) | 1995-04-21 | 1995-06-07 | Speywood Lab Ltd | A novel agent able to modify peripheral afferent function |
GB9617671D0 (en) | 1996-08-23 | 1996-10-02 | Microbiological Res Authority | Recombinant toxin fragments |
US6063768A (en) | 1997-09-04 | 2000-05-16 | First; Eric R. | Application of botulinum toxin to the management of neurogenic inflammatory disorders |
GB9818548D0 (en) | 1998-08-25 | 1998-10-21 | Microbiological Res Authority | Treatment of mucas hypersecretion |
US6767544B2 (en) | 2002-04-01 | 2004-07-27 | Allergan, Inc. | Methods for treating cardiovascular diseases with botulinum toxin |
US6358917B1 (en) | 1999-08-24 | 2002-03-19 | Jean D. A. Carruthers | Cosmetic use of botulinum toxin for treatment of downturned mouth |
GB9922554D0 (en) | 1999-09-23 | 1999-11-24 | Microbiological Res Authority | Inhibition of secretion from non-neuronal cells |
US6113915A (en) | 1999-10-12 | 2000-09-05 | Allergan Sales, Inc. | Methods for treating pain |
US6265379B1 (en) | 1999-10-13 | 2001-07-24 | Allergan Sales, Inc. | Method for treating otic disorders |
US7838008B2 (en) | 1999-12-07 | 2010-11-23 | Allergan, Inc. | Methods for treating diverse cancers |
US6139845A (en) | 1999-12-07 | 2000-10-31 | Allergan Sales, Inc. | Method for treating cancer with a neurotoxin |
US6337075B1 (en) | 2000-01-11 | 2002-01-08 | Allergan Sales, Inc. | Methods for treating diabetes |
US6261572B1 (en) | 2000-01-11 | 2001-07-17 | Allergan Sales, Inc. | Method for treating a pancreatic disorder with a neurotoxin |
US6143306A (en) | 2000-01-11 | 2000-11-07 | Allergan Sales, Inc. | Methods for treating pancreatic disorders |
US6641820B1 (en) | 2000-01-19 | 2003-11-04 | Allergan, Inc. | Clostridial toxin derivatives and methods to treat pain |
US7138127B1 (en) | 2000-01-19 | 2006-11-21 | Allergan, Inc. | Clostridial toxin derivatives and methods for treating pain |
US6524580B1 (en) | 2000-02-15 | 2003-02-25 | Allergan Sales, Inc. | Method for treating thyroid disorders |
US6464986B1 (en) | 2000-04-14 | 2002-10-15 | Allegan Sales, Inc. | Method for treating pain by peripheral administration of a neurotoxin |
US6299893B1 (en) | 2000-04-17 | 2001-10-09 | Marvin Schwartz | Method to reduce hair loss and stimulate hair regrowth |
US6565870B1 (en) | 2000-04-28 | 2003-05-20 | Allergan, Inc. | Methods for treating bone tumors |
US6306403B1 (en) | 2000-06-14 | 2001-10-23 | Allergan Sales, Inc. | Method for treating parkinson's disease with a botulinum toxin |
US6903187B1 (en) | 2000-07-21 | 2005-06-07 | Allergan, Inc. | Leucine-based motif and clostridial neurotoxins |
US6423319B1 (en) | 2000-10-04 | 2002-07-23 | Allergan Sales, Inc. | Methods for treating muscle injuries |
US6827931B1 (en) | 2000-10-20 | 2004-12-07 | Allergan, Inc. | Method for treating endocrine disorders |
US6623742B2 (en) | 2001-09-17 | 2003-09-23 | Allergan, Inc. | Methods for treating fibromyalgia |
US7255866B2 (en) | 2001-09-17 | 2007-08-14 | Allergan, Inc. | Botulinum toxin therapy for fibromyalgia |
US6921538B2 (en) | 2002-05-10 | 2005-07-26 | Allergan, Inc. | Therapeutic treatments for neuropsychiatric disorders |
CA2501856A1 (en) | 2002-10-15 | 2004-04-29 | Allergan, Inc. | Botulinum toxin dental therapies and procedures |
US7238357B2 (en) | 2002-11-05 | 2007-07-03 | Allergan, Inc. | Methods for treating ulcers and gastroesophageal reflux disease |
US8071550B2 (en) | 2003-03-03 | 2011-12-06 | Allergan, Inc. | Methods for treating uterine disorders |
US6838434B2 (en) | 2003-05-02 | 2005-01-04 | Allergan, Inc. | Methods for treating sinus headache |
US7220422B2 (en) | 2003-05-20 | 2007-05-22 | Allergan, Inc. | Methods and compositions for treating eye disorders |
US20040253274A1 (en) | 2003-06-11 | 2004-12-16 | Allergan, Inc. | Use of a clostridial toxin to reduce appetite |
GB0321344D0 (en) | 2003-09-11 | 2003-10-15 | Health Prot Agency | Re-targeted toxin conjugates |
US7514088B2 (en) | 2005-03-15 | 2009-04-07 | Allergan, Inc. | Multivalent Clostridial toxin derivatives and methods of their use |
AU2005279741B2 (en) | 2004-09-01 | 2011-10-06 | Allergan, Inc. | Degradable clostridial toxins |
US20060073208A1 (en) * | 2004-10-01 | 2006-04-06 | Allergan, Inc. | Cosmetic neurotoxin compositions and methods |
GB0425795D0 (en) | 2004-11-24 | 2004-12-22 | Givaudan Sa | Composition |
GB0426397D0 (en) | 2004-12-01 | 2005-01-05 | Health Prot Agency | Fusion proteins |
CA2588292C (en) | 2004-12-01 | 2019-01-15 | Health Protection Agency | Non-cytotoxic protein conjugates |
CA2601577A1 (en) | 2005-03-15 | 2006-09-21 | Allergan, Inc. | Modified clostridial toxins with altered targeting capabilities for clostridial toxin target cells |
DE102005019302A1 (de) | 2005-04-26 | 2006-11-16 | Toxogen Gmbh | Carrier zum Targeting von Nervenzellen |
ES2369558T3 (es) | 2005-09-19 | 2011-12-01 | Allergan, Inc. | Toxinas clostridiales y toxinas clostridiales activables. |
WO2007106115A1 (en) | 2006-03-14 | 2007-09-20 | Allergan, Inc. | Modified clostridial toxins with altered targeting capabilities for clostridial toxin target cells |
GB0610867D0 (en) | 2006-06-01 | 2006-07-12 | Syntaxin Ltd | Treatment of pain |
US20110171191A1 (en) | 2008-06-12 | 2011-07-14 | Syntaxin Limited | Suppression of neuroendocrine diseases |
JP5799397B2 (ja) | 2008-06-12 | 2015-10-28 | イプセン・バイオイノベーション・リミテッドIpsen Bioinnovation Limited | 癌の抑制 |
GB0815264D0 (en) | 2008-08-21 | 2008-09-24 | Syntaxin Ltd | Non-cytotoxic proteins |
GB0820970D0 (en) | 2008-11-17 | 2008-12-24 | Syntaxin Ltd | Suppression of cancer |
EP2419128B1 (en) | 2009-04-14 | 2018-06-06 | Medical College of Wisconsin, Inc. | Engineered botulinum neurotoxin |
US20100303783A1 (en) | 2009-05-29 | 2010-12-02 | Allergan, Inc. | Methods of Treating Urogenital-Neurological Disorders Using Tachykinin Retargeted Endopepidases |
US20100303788A1 (en) | 2009-05-29 | 2010-12-02 | Allergan, Inc. | Methods of Treating Chronic Neurogenic Inflammation Using Galanin Retargeted Endopepidases |
US20100303791A1 (en) | 2009-05-29 | 2010-12-02 | Allergan, Inc. | Methods of Treating Chronic Neurogenic Inflammation Using Glucagon Like Hormone Retargeted Endopepidases |
CN102573877A (zh) | 2009-08-14 | 2012-07-11 | 阿勒根公司 | 使用神经营养蛋白再靶向内肽酶治疗癌症的方法 |
AU2010282278A1 (en) | 2009-08-14 | 2012-03-15 | Allergan, Inc. | Methods of treating cancer using glucagon-like hormone retargeted endopeptidases |
AU2010282273A1 (en) | 2009-08-14 | 2012-03-15 | Allergan, Inc. | Methods of treating cancer using tachykinin retargeted endopeptidases |
EP2464659A1 (en) | 2009-08-14 | 2012-06-20 | Allergan, Inc. | Methods of treating cancer using opioid retargeted endpeptidases |
CA2771289A1 (en) | 2009-08-14 | 2011-02-17 | Allergan, Inc. | Methods of treating cancer using galanin retargeted endpeptidases |
US8853360B2 (en) | 2010-06-23 | 2014-10-07 | Wisconsin Alumni Research Foundation | Engineered botulinum neurotoxin C1 with selective substrate specificity |
US9321847B2 (en) * | 2010-09-20 | 2016-04-26 | Ramot At Tel Aviv University Ltd. | Activatable toxin complexes comprising a cleavable inhibitory peptide |
US20120244188A1 (en) | 2011-03-25 | 2012-09-27 | Allergan, Inc. | Treatment of Sensory Disturbance Disorders |
US20120251575A1 (en) | 2011-03-28 | 2012-10-04 | Allergan, Inc. | Endopeptidase Treatment of Involuntary Movement Disorders |
US20120251574A1 (en) | 2011-03-28 | 2012-10-04 | Allergan, Inc. | Endopeptidase and Neurotoxin Combination Treatment of Multiple Medical Conditions |
US20120251573A1 (en) | 2011-03-28 | 2012-10-04 | Allergan, Inc. | Endopeptidase Treatment of Neuroendocrine Disorders |
US20120251518A1 (en) | 2011-03-29 | 2012-10-04 | Allergan, Inc. | Endopeptidase Treatment of Sexual Dysfunction Disorders |
US20120251519A1 (en) | 2011-03-29 | 2012-10-04 | Allergan, Inc. | Endopeptidase Treatment of Smooth Muscle Disorders |
WO2012135304A1 (en) | 2011-03-29 | 2012-10-04 | Allergan, Inc. | Vagal nerve-based disorders |
GB201108108D0 (en) | 2011-05-16 | 2011-06-29 | Syntaxin Ltd | Therapeutic fusion proteins |
US20140056870A1 (en) | 2012-08-27 | 2014-02-27 | Allergan, Inc. | Fusion proteins |
US9005628B2 (en) | 2012-10-04 | 2015-04-14 | Dublin City University | Biotherapy for pain |
GB201303108D0 (en) | 2013-02-21 | 2013-04-10 | Syntaxin Ltd | Therapeutics for suppressing osteoporosis |
GB201312295D0 (en) | 2013-07-09 | 2013-08-21 | Syntaxin Ltd | Suppression of itch |
US9216210B2 (en) * | 2013-12-23 | 2015-12-22 | Dublin City University | Multiprotease therapeutics for chronic pain |
-
2017
- 2017-09-28 EP EP17781435.7A patent/EP3519430A1/en active Pending
- 2017-09-28 US US16/325,046 patent/US20210277071A1/en not_active Abandoned
- 2017-09-28 JP JP2019517381A patent/JP7118055B2/ja active Active
- 2017-09-28 CN CN201780059944.8A patent/CN109790204A/zh active Pending
- 2017-09-28 WO PCT/EP2017/074665 patent/WO2018060351A1/en unknown
- 2017-09-29 TW TW106133552A patent/TWI796305B/zh active
-
2022
- 2022-03-17 JP JP2022042349A patent/JP2022081642A/ja active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2011045377A (ja) * | 2002-09-12 | 2011-03-10 | Health Protection Agency | 組換え毒素フラグメント |
JP2013139454A (ja) * | 2004-09-06 | 2013-07-18 | Toxogen Gmbh | 神経細胞に化合物を導入するために用いられる輸送タンパク質 |
JP2012519724A (ja) * | 2009-03-09 | 2012-08-30 | ヘンルイ ウイルリアム | シグナルペプチドを担体として有する細菌毒素とのハプテン‐担体抱合体及び免疫原性組成物としてのその使用 |
Non-Patent Citations (4)
Title |
---|
FOSTER KEITH AND CHADDOCK JOHN: "Targeted secretion inhibitors-innovative protein therapeutics.", TOXINS, vol. 2, JPN7021002701, 2010, pages 2795 - 2815, XP055152496, ISSN: 0004805927, DOI: 10.3390/toxins2122795 * |
JOHN A. CHADDOCK ET AL.: "Inhibition of Vesicular Secretion in Both Neuronal and Nonneuronal Cells by a Retargeted Endopeptida", INFECTION AND IMMUNITY, vol. 68(5), JPN7021002700, 2000, pages 2587 - 2593, ISSN: 0004805926 * |
MARGARET R. BUNOW ET AL.: "Phase behavior of ganglicoside-lecthin mixtures relation to dispersion of gangliosides in membranes.", BIOPHYSICAL JOURNAL, vol. 27, JPN7021002702, 1979, pages 325 - 337, ISSN: 0004805928 * |
RUMMEL, ANDREAS ET AL.: "Exchange of the HCC domain mediating double receptor recognition improves the pharmacodynamic proper", FEBS JOURNAL, vol. 278(23), JPN7021002703, 2011, pages 4506 - 4515, ISSN: 0004805929 * |
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JP2022081642A (ja) | 2022-05-31 |
TW201819403A (zh) | 2018-06-01 |
JP7118055B2 (ja) | 2022-08-15 |
WO2018060351A1 (en) | 2018-04-05 |
US20210277071A1 (en) | 2021-09-09 |
CN109790204A (zh) | 2019-05-21 |
RU2019112106A (ru) | 2020-10-29 |
TWI796305B (zh) | 2023-03-21 |
EP3519430A1 (en) | 2019-08-07 |
RU2019112106A3 (ja) | 2021-02-11 |
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