JP6862627B2 - 自然免疫応答疾患を治療するための医薬および方法 - Google Patents
自然免疫応答疾患を治療するための医薬および方法 Download PDFInfo
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- JP6862627B2 JP6862627B2 JP2016536845A JP2016536845A JP6862627B2 JP 6862627 B2 JP6862627 B2 JP 6862627B2 JP 2016536845 A JP2016536845 A JP 2016536845A JP 2016536845 A JP2016536845 A JP 2016536845A JP 6862627 B2 JP6862627 B2 JP 6862627B2
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Description
植物性食物アレルゲンは、クピン(cupin)およびプロラミン(prolamin)スーパーファミリーならびに植物防御系のタンパク質性分子を含む、広く存在するグループの植物タンパク質である。プロラミンスーパーファミリーは、マメ科植物、木の実、穀物、果物、および野菜のいくつかの重要なタイプのアレルゲンならびに穀物アルファ−アミラーゼおよびプロテアーゼ阻害剤を含む。穀物プロラミンは、穀類胚乳の主な貯蔵タンパク質であり、コムギではグルテニンおよびグリアジン、ライムギではセカリン、ならびにオオムギではホルデインと命名されている。タンパク質性アルファ−アミラーゼ阻害剤は、非グルテンタンパク質である。構造的類似性に基づいて、植物起源を有するタンパク質性アルファ−アミラーゼ阻害剤は、レクチン様、ノッチン様、CMタンパク質、Kunitz様、c−プロチオニン様、およびタウマチン様を含む6つのファミリーに通常分類される(Richardson,1990)。CM(クロロホルム−メタノール)タンパク質は、120〜160アミノ酸残基および5つのジスルフィド結合を含有する穀物種子由来の大きなタンパク質ファミリーである。それらは、典型的なダブルヘッドアルファ−アミラーゼ/トリプシンドメインを示す。この特徴は、それらがアルファ−アミラーゼおよびトリプシン様酵素の活性を阻害するのを可能にする。アルファ−アミラーゼ阻害剤0.19は、このファミリーのうちで最も研究された阻害剤のうちの1つであり、それは、広範な特異性を有し、昆虫、鳥、および哺乳動物由来のアルファ−アミラーゼを阻害する。
驚いたことに、本発明者らは、酵素:アスペルギルス・ニガー(Aspergillus niger)アスペルギログルタミン酸ペプチダーゼが、個人の消化器系におけるおよび前記阻害剤を含有する食物マトリックスにおける、アルファ−アミラーゼ/トリプシン阻害剤などの植物アレルゲンを加水分解する大きな可能性を有し、そのため、医薬、健康補助食品として、食物の前処置において、または焼き製品を調製するプロセスにおいて使用することができることを発見した。
活性(HPU/mL)=(ODsample−ODblank/S)×11/30
ここで、
ODsample:サンプルろ液の光学濃度(275nm)
ODblank:サンプルブランクろ液の光学濃度(275nm)
S:1.1μg/mL(mL/μg)のL−チロシン標準溶液のOD
30:インキュベーション時間(分)
11:総容積反応混合物(mL)。
[実施例1:アスペルギルス・ニガー(Aspergillus niger)アスペルギログルタミン酸ペプチダーゼは、模擬胃条件下でコムギ由来アルファアミラーゼ/トリプシン阻害剤を効率的に切断するが、他の酸性エンドプロテアーゼは効率的ではない。]
[材料および方法]
[アスペルギルス・ニガー(Aspergillus niger)からのアスペルギロペプシンIの生産]
アスペルギルス・ニガー(Aspergillus niger)由来のアスペルギロペプシンIについての遺伝子(pepA;An14g04710)を、国際公開第98/46772号パンフレットにおいて記載されるなどの方法を使用して、A.ニガー(A.niger)宿主において過剰発現させた。国際公開第98/46772号パンフレットは、アセトアミドを含有する寒天プレート上で形質転換体を選択するおよび標的多コピー組み込み体を選択する方法を開示する。発現カセットの複数のコピーを含有するA.ニガー(A.niger)形質転換体を、サンプル材料のさらなる生成に選択した。形質転換A.ニガー(A.niger)株は、修飾CSM発酵培地、pH6.2(40g/lマルトース、30g/l Bacto−soytone、70g/lクエン酸三ナトリウム二水和物、15g/l (NH4)2SO4、1g/l NaH2PO4 *2H2O、1g/l MgSO4 *7H2O、1g/l L−Arg、0.25ml/l Clerol Antifoam)において発酵させた。得られた培養ブロスは、ろ過し、滅菌ろ過し、次いで、限外ろ過によって濃縮した。50mmol/l酢酸Na、pH5.6中のQ−セファロースXK 26/10カラムに酵素を加え、その後、塩勾配での溶出によって、クロマトグラフィーを実行した。様々な画分におけるアスペルギロペプシンIタンパク質の存在は、4〜12%SDS−PAGE(NuPAGE Bis−Tris Gel、Invitrogen)の後に着色したタンパク質バンドの強度を判断することにより定量化した。
インキュベーションは、37℃で90分間、pH4.0の50mmol/l クエン酸Na中で実行した。すべての関連するインキュベーションにおいて、ペプシンは、0.2mg/mlの酵素タンパク質濃度で存在した。プロリン特異的エンドプロテイナーゼは、0.5mg酵素タンパク質/mlの濃度で試験し、他の酸性エンドプロテイナーゼは、0.05mg酵素タンパク質/mlの濃度とした。アミラーゼ阻害剤は、最後に追加し、2mg/mlの濃度で存在した。
ウシ血液由来の20.0gヘモグロビン(Sigma製品H2625)を、室温で10分間撹拌することによっておよそ700mLの水に懸濁した。3.73g塩化カリウム(KCl)の追加後、pHを0.5mol/Lの塩酸により1.75に調節した。ヘモグロビン懸濁液の容量を水により1Lに調節した。pHをもう一度確認し、pH1.75に調節した。
活性(HPU/mL)=(ODsample−ODblank/S)×11/30
ここで、
ODsample:サンプルろ液の光学濃度(275nm)
ODblank:サンプルブランクろ液の光学濃度(275nm)
S:1.1μg/mL(mL/μg)のL−チロシン標準溶液のOD
30:インキュベーション時間(分)
11:総容積反応混合物(mL)。
[インビトロにおける消化]
サンプルを、MilliQ水に1mg/mlまで溶解した。溶液を、100mM NH4HCO3(pH7.8)中に10×に希釈した。サンプルは、DTT、5mMの追加、室温での30分間のインキュベーションによって還元し、ヨードアセトアミド(IAA)、5.5mMの追加、暗中、室温での30分間のインキュベーションによってアルキル化した。トリプシンによる消化を、一晩、37℃で実行した。
ゲルバンドは、ExQuestスポットカッター(Biorad、Hercules、CA、USA)を使用してゲルから切り取り、lo−protein bind MTP(Eppendorf、Hamburg Germany)の中に移した。ゲル片は、膨脹させるための75μl 50mM NH4HCO3および収縮させるための75μlアセトニトリルを追加することによって洗浄し、合計3回洗浄した。洗浄したゲル片は、トリプシン消化により消化し、一晩37℃でのインキュベーションを行った。サンプルを1分間超音波処理し、上清を注入バイアルの中に収集した。
サンプルを1%ギ酸に酸性化し、Accela−LTQ−Velos(Thermo Scientific、San Diego、CA、USA)で分析した。クロマトグラフィーによる分離は、2.1×100mm 1.8マイクロメートルの粒径、80Åポアサイズ、C−18 Eclipse XDB Zorbaxカラム(Agilent Santa Clara、CA、USA)により、移動相として(A)0.1%ギ酸を含有するLC−MS級水B)0.1%ギ酸溶液を含有するLC−MS級アセトニトリル(Biosolve BV、Netherlands)による勾配溶離を使用して実現した。勾配は、83分間5〜40% Bとした。流速は、25μlの注入量を使用して、0.4ml/分に保ち、カラム温度は50℃にセットした。MSデータ収集は、ダイナミックエクスクルージョン(Dynamic exclusion)を使用し、電荷状態2および3のみを含め、質量範囲400〜2000m/zによる上位10のデータ依存性の収集を使用して実行した。MS/MS実験を、3.0にセットした単離幅で実行し、標準衝突エネルギーは35にセットした。データベース検索は、好ましい酵素としてトリプシンを使用し、Sorcerer 2(Sorcerer(商標)−SEQUEST(登録商標))検索エンジンおよびTrans Proteome Pipeline(TPP)を使用して実行した。信頼度>90%で同定されたタンパク質のみを考慮した。データは、Swissprotデータベースに対して検索した。
本発明の実施例において、発明者らは、模擬胃条件下で、多くの酸性エンドプロテイナーゼの中でアスペルギルス・ニガー(Aspergillus niger)アスペルギログルタミン酸ペプチダーゼのみが、様々なコムギアルファ・アミラーゼ阻害剤(コムギ種子由来のアルファアミラーゼ阻害剤、1型、Sigma)を組み込む精製調製物を効率的に分解することができることを実証する(図1を参照されたい)。実験において、以下の酵素の効率を、ペプシン(コントロール)の存在下において比較した:
− ペプシン(ブタ胃粘膜、Sigma)、
− アスペルギルス・ニガー(Aspergillus niger)由来のプロリン特異的エンドプロテイナーゼ(MaxiPro PSP、DSM Food Specialities、Delft、Netherlands)
− パパイン(Collupuline、DSM Food Specialities、Delft、Netherlands)、
− アスペルギロペプシンIIとも呼ばれるアスペルギルス・ニガー(Aspergillus niger)アスペルギログルタミン酸ペプチダーゼ(MaxiPro HSP、DSM Food Specialities、Delft、Netherlands)、
− アスペルギロペプシンI(材料および方法を参照されたい)、
− Multifect PR 15 L(トリコデルマ・リーゼイ(Trichoderma reesei)由来のアスペルギロペプシンI様プロテアーゼ;http//biosciences.dupont.com)。
それらのアミノ酸配列によれば、オオムギは、コムギ中に存在するアルファアミラーゼ阻害剤に非常に類似するアルファアミラーゼ阻害剤を組み込む。そのため、ビールは、グルテン感受性の個人に関連し得る食品をもたらす。ビールにおいて、他の食品におけるように、アルファアミラーゼ阻害剤は、完全な分子または免疫応答を誘起するのに十分に大きなペプチドとして存在する。たとえば、16種の異なるビールのLC−MS/MS分析において、発明者らは、アルファアミラーゼ阻害剤に帰する配列を有する9アミノ酸よりも大きな約3300種の異なるペプチドを同定した。この発見は、グルテン感受性の個人についてのアルファアミラーゼ阻害剤の関連の可能性、それによって、ビール生産についてのアスペルギログルタミン酸ペプチダーゼの関連を示す。
本発明の実施例において、発明者らは、模擬胃条件下で、1グラムのコムギグルテン中に存在するアルファアミラーゼ/プロテアーゼ阻害剤を加水分解するために必要とされるA.ニガー(A.niger)アスペルギログルタミン酸ペプチダーゼ酵素タンパク質の量を決定する。その目的のために、コムギ由来のグルテン(Sigma)を、9.35mg/mlの濃度で50mmol/lクエン酸pH4.0中で可溶化した。この完全に撹拌した混合物に、ペプシン酵素タンパク質を追加し、0.2mg/mlの最終濃度に達し、次いで、6つの1mlサンプルを得た。これらの6つのサンプルに、増加性の量の純粋なA.ニガー(A.niger)アスペルギログルタミン酸ペプチダーゼ酵素を追加した。サンプル1にはAGPを追加せず、サンプル2には0.09mg、サンプル3には0.19mg、サンプル4には0.28mg、サンプル5には0.37mg、最後のサンプルには0.47mgを追加した。次いで、様々なサンプルを、摂氏37度で60分間インキュベートし、それぞれのサンプルから、SDS−PAGE分析用の一定分量を、t=0分およびt=60分に得た。SDS−PAGE分析をInvitrogenプロトコールに従って実行した。
[材料および方法]
プロチオニンを、いくらか修飾してOhtani et al(J.Biochem.82,753−767(1977))によって記載されるように単離した。コムギ上清は、20ミリモル/lリン酸ナトリウム、pH7.2により平衡化したSP Sepharose 6 FF(Amersham)でクロマトグラフィーによって分離し、同バッファー中0〜1.0モル/l NaClの直線勾配により溶出した。様々な画分におけるおよそ5kDaの分子量を有する純粋なプロチオニンの存在をSDS−PAGEによって追った。単一のタンパク質バンドを示す画分をプールし、Amicon 3kDa膜を使用して濃縮し、次いで、凍結乾燥した。単離されたタンパク質の特徴および純度は、Uniprot/Swissprotデータベースを使用して、本質的に実施例1において記載されるように、LC−MS/MS分析によって確認した。
様々なプロテアーゼとの精製プロチオニンのインキュベーションは、本出願の実施例1において指定される条件と同様に37℃で90分間pH4.0の50mmol/l Naクエン酸中で実行した。すべての関連するインキュベーションにおいて、ペプシンは、0.2mg/mlの酵素タンパク質濃度で存在した。アスペルギログルタミン酸ペプチダーゼ、プロリン−特異的エンドプロテイナーゼ、およびMultifect PR 15 Lは、0.11mg酵素タンパク質/mlの濃度で試験した。コムギプロチオニンは、最後に追加し、0.44mg/mlの濃度で存在した。
実験において、以下の酵素の効率を、ペプシンの存在下において比較した:
− アスペルギロペプシンIIとも呼ばれるアスペルギルス・ニガー(Aspergillus niger)アスペルギログルタミン酸ペプチダーゼ(MaxiPro HSP、DSM Food Specialities、Delft、Netherlands)、
− アスペルギルス・ニガー(Aspergillus niger)由来のプロリン特異的エンドプロテイナーゼ(MaxiPro PSP、DSM Food Specialities、Delft、Netherlands)
− Multifect PR 15 L(トリコデルマ・リーゼイ(Trichoderma reesei)由来のアスペルギロペプシンI様プロテアーゼ;http//biosciences.dupont.com)。
[材料および方法]
プロチオニンは、実施例4において記載されるようにコムギから単離した。プロクターゼは、明治(Meiji)(東京(Tokyo)、日本(Japan))から得た。
図5におけるコムギプロチオニンの消化産物によって示されるように、アスペルギルス・ニガー(Aspergillus niger)由来のアスペルギロペプシンIまたはトリコデルマ・リーゼイ(Trichoderma reesei)由来のそのホモログを組み込む酵素産物は、模擬胃条件下でコムギプロチオニンを加水分解することができる。
ビールは、コムギ中に存在するアレルゲン性アルファ−アミラーゼ/トリプシン阻害剤に非常に相同性であることが知られているオオムギ由来アルファ−アミラーゼ/トリプシン阻害剤を組み込む(Okada et al,J.Agric.Food Chem.2008,56,1458−1464)。本出願の実施例1において示される結果は、アスペルギログルタミン酸ペプチダーゼが様々なアルファ−アミラーゼ/トリプシン阻害剤を有効に加水分解することができることを示す。そのため、ビールへのアスペルギログルタミン酸ペプチダーゼの追加に際して、オオムギ由来のアルファ−アミラーゼ/トリプシン阻害剤もまた加水分解されることを期待することができる。実施例2では、発明者らは、関連する酸性プロテアーゼの追加が、ビール気泡の質にマイナスの効果を有していないことを示す。本発明の実施例において、発明者らは、アルファ−アミラーゼ/トリプシン阻害剤およびタンパク質Z(Garcia−Casado et al.,J Allergy Clin Immunol,108(4),pp647−649)のような既知のビールアレルゲンを加水分解するために必要とされるアスペルギログルタミン酸ペプチダーゼ、アスペルギロペプシンI、およびトリコデルマ・リーゼイ(Trichoderma reesei)のアスペルギロペプシンIホモログの適量の酵素が、ビール気泡安定性に対して有害作用を有していない、寒冷混濁を予防するために必要とされる多量のプロリン特異的エンドプロテアーゼ(MaxiPro PSP、DSM Food Specialities、Delft、Netherlands)と組み合わせてでさえ有していないことを示す。
Claims (11)
- アスペルギルス・ニガー(Aspergillus niger)アスペルギログルタミン酸ペプチダーゼ、アスペルギルス・ニガー(Aspergillus niger)プロリルエンドペプチダーゼ、および薬学的にまたは食事療法で許容され得る賦形剤を含む健康補助食品または医薬組成物。
- 前記医薬組成物がアスペルギロペプシンIをさらに含む、請求項1に記載の健康補助食品または医薬組成物。
- 前記健康補助食品が、錠剤、カプセル、または液体製剤の形態をしている、請求項1または2に記載の健康補助食品または医薬組成物。
- 健康補助食品または医薬組成物の製造のためのアスペルギルス・ニガー(Aspergillus niger)アスペルギログルタミン酸ペプチダーゼの使用であって、アスペルギルス・ニガーアスペルギログルタミン酸ペプチダーゼは、アスペルギルス・ニガー(Aspergillus niger)プロリルエンドペプチダーゼとともに用いられることを特徴とする、使用。
- 前記健康補助食品または医薬組成物が、薬学的にまたは食事療法で許容され得る賦形剤をさらに含む、請求項4に記載の使用。
- 前記医薬組成物が、アスペルギロペプシンIをさらに含む、請求項4または5に記載の使用。
- 前記医薬組成物が、腸における自然免疫応答に苦しんでいる患者の治療のためのものである、請求項4〜6のいずれか一項に記載の使用。
- 前記医薬組成物が、セリアック病、非セリアック病グルテン不耐性、グルテン感受性、過敏性腸症候群、または炎症性腸疾患の治療のためのものである、請求項4〜7のいずれか一項に記載の使用。
- 前記健康補助食品が、グルテン感受性の個人における胃腸の快適さを維持もしくは増強するための、またはセリアック病もしくは非セリアック病グルテン感受性の個人における胃腸の不快感の発病を遅延させるための、ならびに健康な個人におけるアルファ−アミラーゼ/トリプシン阻害剤暴露を減少させるためのものである、請求項4〜6のいずれか一項に記載の使用。
- 前記健康補助食品が、食事の前または後の1時間以内に経口的に投与される、請求項4〜6及び9のいずれか一項に記載の使用。
- 前記医薬組成物が、食事の前または後の1時間以内に経口的に投与されるものである、請求項4〜8のいずれか一項に記載の使用。
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