JP5357425B2 - 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 - Google Patents
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 Download PDFInfo
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Description
ボツリヌス菌神経毒B型タンパク質(データベース番号AAA23211)、アミノ酸1079〜1291、
ボツリヌス菌神経毒C1型タンパク質(データベース番号CAA51313)、アミノ酸1093〜1291、
ボツリヌス菌神経毒D型タンパク質(データベース番号CAA38175)、アミノ酸1080〜1276、
ボツリヌス菌神経毒E型タンパク質(データベース番号CAA44558)、アミノ酸1067〜1252、
クロストリジウム・ブチリカム(Clostridium butyricum)神経毒E型タンパク質(データベース番号CAA43998)、アミノ酸1067〜1251、
ボツリヌス菌神経毒F型タンパク質(データベース番号CAA57358)、アミノ酸1085〜1278、
クロストリジウム・バラティー(Clostridium baratii)神経毒F型タンパク質(データベース番号CAA48329)、アミノ酸1076〜1268、
ボツリヌス菌神経毒G型タンパク質(データベース番号CAA52275)、アミノ酸1087〜1297
の配列によって置換されている、輸送タンパク質に関する。
PCRによって、BoNT/AのHCのDNA配列をボツリヌス菌の染色体DNA(データベース番号AAA23262)において増幅した。このために、特異的オリゴヌクレオチドによって、アミノ酸チロシン1117のコドンを、アラニンのアミノ酸残基をコードする塩基トリプレットによって置換した。さらに、遺伝子の5’末端に、トロンビンの認識配列のアミノ酸をコードするDNA配列を加えた。このDNA配列を、細菌発現ベクターに挿入した。挿入されるTrapoの遺伝子は、この場合には、3’末端でカルボキシ末端親和性ペプチドをコードするオリゴヌクレオチド、例えば、Strep−day、6xHN−dayまたはHis6−dayと融合させた。このように作製した発現ベクターpAR−Trapoが、BoNTのLCなどの担体分子を加えるための開始基礎である。
放射活性物質によって標識されたHC−断片の、ラットシナプトソームとの結合を、ルメル(Rummel)ら、ジャーナル・オブ・モレキュラー・バイオロジー(Journal of Molecular Biology)326(2003)、835〜847頁に記載されるとおりに測定した。BoNT/A変異体の神経毒性は、ハーバーマン(Habermann)ら、ナウニン・シュミーデベルグス・アーカイブ・オブ・ファルマコロジー(Naunyn Schmiedeberg's Archives of Pharmacology)311(1980)、33〜40頁に記載されるとおりに求めた。
結合および神経毒性の測定を、上記のとおりに実施した。
メタノールにガングリオシドGT1b[NAcNeuα3GalβNAcGalβ4(NAcNeuα8NAcNeuα3)Galβ4Glcβ](シグマ−アルドリッチ(Sigma-Aldrich))を溶解し、高親和性96カップポリスチレンマイクロタイタープレート(コーニング(Corning);100μl/カップ中1μgGT1b)に適用するか、競合アッセイの場合には、125I−BoNT(グレイナー・バイオ−オーン(Greiner Bio-ohne);100μl/カップ中0.1μgGT1b)を含む高親和性CSシングルフラクチャー(single fracture)ストリッププレートに適用する。溶媒を室温で蒸発させ、カップを結合バッファー(10mM Tris−HCl、10mM Na2HPO4、0.5%BSA、pH7.2)で3回リンスする。次いで、3%(w/v)BSAを補給したPBS/Tween[140mM NaCl、7mM KCl、10mM Na2HPO4、1.8mM KH2PO4、0.05%(v/v)Tween20、pH7.2]中で2時間インキュベートすることによって非特異的結合部位をブロッキングする。結合アッセイは、野生型の量または変異体の比状態量を漸増させて、結合バッファー(100μl/カップ)中、室温で2時間実施する。各250μlのPBS/Tweenバッファーを用いる3回のリンスステップにおいて結合していないタンパク質を除去する。製造業者の使用説明書に従い、結合バッファー中でアルカリホスファターゼと結合しているストレップタクチン(Strep Tactin)(ST−AP、IBA社(IBA GmbH))とともに、室温で2時間インキュベートすることによって、結合しているHC−断片を同定する。最終的にアルカリホスファターゼの基質として働くp−ニトロフェニルホスフェート(100mMグリシン、1mM MgCl2、1mM ZnCl2、pH10.4中1mg/ml)。3M NaOH溶液を添加することによって脱リン酸化反応を停止し、スペクトラカウントマイクロプレートリーダー装置(パッカード(packard))を用いて405nmで吸光度を測定する。競合アッセイは、700000cpm/カップ[125I]−BoNT、種々の量の天然BoTNまたは組換えHC−断片を含む結合バッファー100μl中、室温で2時間かけて実施する。インキュベートし、上清を除去した後、カップをPBS/Tweenバッファーで3回リンスし、乾燥させ、分離する。次いで、結合している放射活性物質によって標識されたBoNTの量を、自動γカウンター(ワラック(Wallac)1480ウィザード(Wizard)3)で測定する。
Claims (35)
- ボツリヌス菌によって形成される神経毒の重鎖の改変によって得られる輸送タンパク質であって、
前記神経毒がボツリヌス神経毒A型(BoNT/A)であり、前記タンパク質が天然の神経毒よりも高い親和性で神経細胞と結合し、
前記タンパク質が、原形質膜に局在する、コリン作動性運動ニューロンの複合体ガングリオシドと特異的に結合し、
配列番号1に記載のボツリヌス神経毒A型タンパク質配列の位置1117、1252、1253、1270、1278、1279に対応する位置の少なくとも1個のアミノ酸が、天然に生じるアミノ酸もしくは非天然起源のアミノ酸のいずれかによって置換されている、
輸送タンパク質。 - 神経細胞と特異的に結合し、エンドサイトーシスによって細胞に入る、請求項1に記載の輸送タンパク質。
- 原形質膜に局在する、コリン作動性運動ニューロンの複合体ガングリオシドがGT1bである、請求項1に記載の輸送タンパク質。
- 輸送タンパク質のガングリオシド結合ドメインが、親和性の増加に影響を及ぼすアミノ酸の置換を含む、請求項3に記載の輸送タンパク質。
- 天然の神経毒よりも少なくとも15%高い親和性を示す、請求項1から4のいずれか一項に記載の輸送タンパク質。
- 天然の神経毒よりも少なくとも50%高い親和性を示す、請求項5に記載の輸送タンパク質。
- 天然の神経毒よりも少なくとも80%高い親和性を示す、請求項6に記載の輸送タンパク質。
- 天然の神経毒よりも少なくとも90%高い親和性を示す、請求項7に記載の輸送タンパク質。
- 配列番号1に記載のボツリヌス神経毒A型タンパク質配列の位置1117に対応する位置のアミノ酸が、天然に生じるアミノ酸もしくは非天然起源のアミノ酸のいずれかによって置換されている、請求項1に記載の輸送タンパク質。
- 置換されるアミノ酸が、アラニン、システイン、グルタミン酸、フェニルアラニン、イソロイシン、ロイシン、メチオニン、アスパラギン、プロリン、グルタミン、セリン、トレオニンまたはバリンのいずれかである、請求項9に記載の輸送タンパク質。
- 置換されるアミノ酸が、アラニン、システインまたはバリンである、請求項9に記載の輸送タンパク質。
- 配列番号1に記載のボツリヌス神経毒A型タンパク質配列の位置1252に対応する位置のアミノ酸がチロシンによって置換されるか、位置1253に対応する位置のアミノ酸がリジンによって置換される、請求項1に記載の輸送タンパク質。
- 配列番号1に記載のボツリヌス神経毒A型タンパク質配列の位置1117、1202〜1204、1252〜1254、1270および1278〜1279に対応する位置から選択される2または3個のアミノ酸が置換される、請求項1に記載の輸送タンパク質。
- 配列番号1に記載のボツリヌス神経毒A型タンパク質配列の位置1117/1252、1117/1253、1117/1262、1117/1278、1117/1279、および1117/1252/1253に対応する位置から選択される2または3個のアミノ酸が置換される、請求項1に記載の輸送タンパク質。
- 配列番号1に記載のボツリヌス神経毒A型タンパク質配列の位置Y1117A/F1252Y、Y1117A/H1253K、Y1117A/V1262I、Y1117A/L1278H、Y1117A/G1279N、Y1117C/F1252Y、Y1117C/H1253K、Y1117C/V1262I、Y1117C/L1278H、Y1117C/G1279N、Y1117V/F1252Y、Y1117V/H1253K、Y1117V/V1262I、Y1117V/L1278H、Y1117V/G1279N、Y1117A/F1252Y/H1253K、Y1117C/F1252Y/H1253KおよびY1117V/F1252Y/H1253Kに対応する位置から選択される2または3個のアミノ酸が置換される、請求項1に記載の輸送タンパク質。
- 請求項1から15のいずれか一項に記載の輸送タンパク質と、少なくとも1種の介在分子を含み、前記介在分子が小さい有機分子、ペプチドまたはタンパク質のいずれかを含む組成物。
- 介在分子がペプチド結合、エステル結合、エーテル結合、スルフィド結合、ジスルフィド結合または炭素−炭素結合によって、輸送タンパク質と共有結合している、請求項16に記載の組成物。
- 小さい有機分子がウイルス増殖抑制剤、細胞増殖抑制剤、抗生物質または免疫グロブリンである、請求項16に記載の組成物。
- タンパク質がプロテアーゼを含む、請求項16に記載の組成物。
- プロテアーゼがボツリヌス菌A、B、C1、D、E、FおよびG型の神経毒タンパク質を含む、請求項19に記載の組成物。
- プロテアーゼが、ボツリヌス菌A、B、C1、D、E、FおよびG型のタンパク質に由来するタンパク質分解的に活性な断片を含む、請求項19に記載の組成物。
- プロテアーゼがコリン作動性運動ニューロン内の特異的基質を開裂し、前記基質が、末梢神経における神経伝達物質の放出に関与するタンパク質から、および神経細胞内で反応を触媒できるタンパク質から選択される、請求項21に記載の組成物。
- プロテアーゼと輸送タンパク質が、エンドペプチダーゼによって特異的に認識され開裂されるアミノ酸配列によって、共有結合されている、請求項22に記載の組成物。
- エンドペプチダーゼによる開裂後、ジスルフィド架橋がプロテアーゼと輸送タンパク質を連結し、これが次いで、活性なホロ毒素の形成をもたらす、請求項23に記載の組成物。
- 請求項1から15のいずれか一項に記載の輸送タンパク質、または、請求項16から24のいずれか一項に記載の組成物を含有する薬剤組成物。
- 製薬上許容される賦形剤、希釈剤および/または添加物をさらに含有する、請求項25に記載の薬剤組成物。
- ボツリヌス神経毒を用いる療法が指示される非ヒト動物の障害または疾患を治療するための、請求項25または26に記載の薬剤組成物の使用。
- 障害または疾患が以下:片側顔面痙攣、痙性斜頸、痙縮、ジストニア、片頭痛、疼痛、頚部および腰椎柱の障害、斜視、流涎過多および鬱病性疾患のうち1種である、請求項27に記載の使用。
- 請求項1から15のいずれか一項に記載の輸送タンパク質、または、請求項16から24のいずれか一項に記載の組成物を含有する化粧料組成物。
- 化粧料に許容される賦形剤、希釈剤および/または添加物をさらに含有する、請求項29に記載の化粧料組成物。
- 化粧料の適応症が多汗症および極めて顕著な顔面のしわである、請求項29または30に記載の化粧料組成物。
- 公知の方法による組換えによる、請求項1から15のいずれか一項に記載の輸送タンパク質、または、請求項16から24のいずれか一項に記載の組成物の製造方法。
- 請求項1から15のいずれか一項に記載の輸送タンパク質、または、請求項16から24のいずれか一項に記載の組成物をコードする組換え発現ベクターを含む宿主細胞。
- 宿主細胞が大腸菌(Escherichia coli)、サッカロミセス・セレビシエ(Saccharomyces cerevisiae)、ピキア・パストリス(Pichia pastoris)または巨大菌(Bacillus megaterium)の細胞であり得る、請求項33に記載の宿主細胞。
- 請求項1から15のいずれか一項に記載の輸送タンパク質、または、請求項16から24のいずれか一項に記載の組成物をコードする核酸を含む発現ベクター。
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