JP2018533544A - 合成リガンドまたはアルギニル化bipのp62 zzドメインへの結合を介した、オートファジー活性による神経変性疾患の抑制および処置 - Google Patents
合成リガンドまたはアルギニル化bipのp62 zzドメインへの結合を介した、オートファジー活性による神経変性疾患の抑制および処置 Download PDFInfo
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Abstract
Description
以後、本発明を詳細に記載する。
配列番号2:Arg−Ala;
配列番号3:Phe−Ala;
配列番号4:Trp−Ala;
配列番号5:Tyr−Ala;
配列番号6:Arg−Ile−Phe−Ser−Thr−Ile−Glu−Gly−Arg−Thr−Tyr−Lys(R−11);
配列番号7:Trp−Ile−Phe−Ser−Thr−Ile−Glu−Gly−Arg−Thr−Tyr−Lys(W−11);
配列番号8:BiPタンパク質のN−末端のGlu19がアルギニル化されている(R−BiP);および
配列番号9:アルギニル化されたBiP N−末端ペプチド(R−BiPD)。
[式1]
[式5]
しかしながら、当業者は、本開示を考慮すれば、本発明の意図および範囲を逸脱することなく改変および改善し得ることが理解されるであろう。
N−デグロンに結合する新規N−レコグニンを同定するため、N−末端にN−デグロンを付加うすることにより、ペプチドを合成した。次いで、ラット組織抽出物中で、合成されたペプチドに結合し得るタンパク質の種類を調べた。
例<1−1>におけるp62タンパク質をより明確に同定するため、以下の実験を行った。
Arg(R)、His(H)およびLys(K)は、正電荷を持つ側鎖を有し、一方で、Phe(F)、Trp(W)およびTyr(Y)は、芳香族側鎖を有する。p62に結合するアミノ酸の特徴から、p62は、正に荷電しているかまたは、芳香族側鎖を好む可能性があることが確認された。p62は、Val(V)、Leu(L)およびGly(G)などの疎水性側鎖を有するアミノ酸、ならびにAsp(D)などの負に電荷している側鎖を有するアミノ段を好まなかった。上記結果は、p62が、Nt−Arg、Nt−Trp、Nt−Phe、およびNt−Tyrに選択的に結合することを意味する。
p62のNt−ArgおよびNt−Pheに対する結合定数を決定するために以下の実験を行った。
Nt−Argが結合するp62の位置を調べるため、一連のp62の欠失変異体(D1〜D8)を構築し、R11およびW11に対するこれらの結合を、例1に記載されているのと同じ方法によるX−ペプチドプルダウンアッセイによって確認した。
UBRボックスは、UBR1〜UBR7として指定されているN−末端則E3ファミリーに存在する基質認識ドメインである70残基から構成されている。p62 ZZドメインの一次配列を、ClustalWプログラムを用いることにより、種々の生物に由来するUBR E3リガーゼのUBR領域配列と比較した。
N−リガンドArg−Alaが、p62 ZZドメインへ結合することにより、p62の自己オリゴマー化および凝集体形成を誘導することができるかどうかを調べるため、全長p62を発現させたHEK293細胞溶解物を用いてインビトロオリゴマー化アッセイを行い、非還元SDS−PAGEを行った(図8)。
p62のオリゴマー化を誘導するために、ZZドメインがArg−Alaへ結合することが必要かどうかを調べるため、Arg−11ペプチドに結合することができないp62 ZZ変異体を用いてp62オリゴマー化アッセイを行った。
p62のオリゴマー化は、まずオートファゴソーム開始部位へのp62の送達が必要とされ、次いでLC3とp62のオリゴマーとの相互作用を介して、自己小胞体の膜へ導入される(Itakura et al., 2011)。p62のLC3への結合におけるArg−Alaの効果を確認するため、ELISAを行った(図8f−h)。
p62 ZZドメインの生理的N−リガンドであるNt−Argは、ATE1 R−トランスフェラーゼによるN−末端アルギニル化を介して生成されるため、小胞体タンパク質のN−末端配列を、バイオインフォマティクスを用いて調べた。
N−末端アルギニル化BiP(R−BiP)、カルレティキュリン(R−CRT)、およびタンパク質ジスルフィドイソメラーゼ(R−PDI)を特異的に認識する抗体を構築するため、REEEDKKEDVG(R−BiP)、REPAVYFKEQ(R−CRT)、およびRDAPEEEDHVL(R−PDI)などのこれらN−末端アルギニル化タンパク質のN−末端に対応するペプチドを合成した。これらのペプチドをウサギに接種し、抗体血清を得た。抗体はIgGクロマトグラフィーにより精製した。抗体群は、非特異的抗体を除くために、リガンドとしてEEEDKKEDVGC、EPAVYFKEQ、およびDAPEEEDHVLなどの非アルギニル化ペプチドを用いたクロマトグラフィーに通した。最後に、アルギニル化特異的抗体は、リガンドとしてREEEDKKEDVGC(R−BiP)、REPAVYFKEQ(R−CRT)、およびRDAPEEEDHVL(R−PDI)などのアルギニル化ペプチドを用いたクロマトグラフィーに通すことにより精製した(図10b)。
ATE1 R−トランスフェラーゼイソメラーゼを過剰発現させ、次いでR−BiP形成をR−BiP抗体を用いて調べた(図10d)。siRNAを用いてATE1をノックダウンした場合、R−BiPの形成は減少した(図10e)。さらに、Ub−X−BiPフラグ(X=GluまたはVal)を過剰発現させて、アルギニル化を調べた(図11a)。Ub−X−BiP−フラグは、翻訳と同時に脱ユビキチン化酵素によりUbとX−BiP−フラグに変換される。組み換えタンパク質を用いることで、X−BiPのNt−Glu19は、アルギニル化される残基であることが明らかになった(図11a)。
R−BiP生成の原因を調べるため、小胞体タンパク質のN−末端アルギニル化を引き起こし得るストレスを種々の方法で調べた。
R−BiPおよびp62のオートファゴソームへの同時輸送を観察するため、免疫染色を行った。
細胞においてUb−X−BiP−GFP組み換えタンパク質(X=Arg、Glu、またはVal)を過剰発現することによりX−BiP−GFPを生成し(図14a)、その移動を調べるため、免疫染色を行った。R−BIPは、オートファゴソームに移行した(図14c)。一方、Val−BiP(アルギニル化の基質としては用いることができないようにNt−Glu19がValで置換されている)は、Nt−Argがないためにオートファゴソームに移行しなかった(図14c)。LC3の斑点と比較すると、R−BiPの細胞内局在は、LC3のそれと一致していた(図14d)。BiPタンパク質のもう一つの領域がオートファジーのターゲティングに影響を与えることができるので、BiPのほとんどの領域が除去され19〜124の範囲の残基配列のみが残っているUb−X−BiPΔ(図14a)を過剰発現させた。ついで、BiPΔの細胞内局在を調べるため、免疫染色を行った(図14e)。結果として、p62+/+細胞においてはR−BiPΔは斑点を形成し、オートファゴソームに移動することが確認された(図14e)。正常にオートファゴソームに移動できるようにp62+/+細胞においてアルギニル化され得るE−BiPΔは、p62−/−細胞においてオートファゴソーム移動しなかった(図14e)。X−BiPおよびLC3の細胞内局在は、免疫染色により調べた。結果は、上記と一致していた(図14f)。したがって、これらの結果により、BiPまたは他の小胞体タンパク質が細胞質に移行すると、(ミスフォールドタンパク質または他の基質に結合した後に)アルギニル化され、翻訳後修飾により生成されるNt−Argが、p62 ZZドメインに結合するためのN−リガンドとして作用することが確認された。
R−BiP Nt−Argがp62 ZZドメインに結合し得るかどうかを調べるため、X−ペプチドプルダウンアッセイを行った(図15aおよびb)。
R−BiPがp62を介したオートファジーにより分解されるかどうかを調べるため、Ub−X−BiPΔ−GSTを構築し、次いでp62+/+およびp62−/−細胞において過剰発現させた(図16a)。
R−BiPを誘導するストレスの種類を調べるため、細胞を種々の化学物質で処理し、イムノブロッティングを行ってR−BiPの形成を調べた。
細胞をゲルデナマイシン(Hsp90阻害剤)で処理し、細胞内ミスフォールドタンパク質の形成を促進した。
p62 ZZドメインリガンドをさらに同定するために、研究を行って、N−末端則リガンドであるNt−Trpに対して構造的類似性を有する小化合物2−((3,4−ビス(ベンジルオキシ)ベンジル)アミノ)エタン−1−オール塩酸塩(ZZ−L1と名付けた;式5)および1−(3,4−ビス(ベンジルオキシ)フェノキシ)−3−(イソプロピルアミノ)−2−プロパノール(ZZ−L2と名付けた;式6)が、p62活性、特に、オリゴマー化およびオートファジー活性を促進することを確認した。ZZ−L2は、NCI314953として知られている物質である。これらの低分子量化合物は、Arg−AlaよりもむしろPhe−AlaまたはTrp−Alaに対して構造的類似性を有するため、ZZドメインのタイプ2結合サブドメインに結合する。
ZZ−L1およびZZ−L2のオートファジーにおける効果を調べるため、ウェスタンブロッティングを行った。
ZZリガンド処理により誘導されるLC3合成およびLC3−II形成の増加は、オートファゴソーム形成におけるオートファジーフラックスの上流(主要因子の合成および翻訳)または下流(オートファゴソームおよびリソソームの融合またはリソソームおける分解プロセス)のいずれかの活性化に起因することができた。ZZリガンドで処理した細胞においてオートファジーフラックスが正常であるかどうかを調べるため、細胞をまたオートファジー阻害剤で処理した。次いで、LC3レベルを測定するため、イムノブロッティングを行った。リソソーム分解阻害剤として作用するNH4Cl(Sigma, A9434)、バフィロマイシンA1(Sigma, B1793)、およびヒドロキシクロロキン(HCQ)(Sigma, H0915)を用いることにより、オートファジーフラックスアッセイを行った(図19e)。細胞をXIE ZZ化合物で3時間処理し、これにオートファゴソーム阻害剤を処理してさらに3時間培養した。細胞溶解液を用いてウェスタンブロッティングを行った。LC3−IIバンドの強度は、imageJを用いて測定した。LC3−II形成の増加は、GAPDHで正規化して計算した。
ZZリガンドにより誘導されたオートファゴソームがリソソームに送達されるかどうかを調べるため、その中に酸感受性GFPおよび非感受性RFPを組み合わせたRFP−GFP−LC3を安定的に形質導入したHeLa細胞を用いる実験において用いられたのと同じ方法で、オートファジー動態アッセイを行った。
これまで知られている最も代表的なオートファジー活性化剤は、ラパマイシンである。ラパマイシンは、mTOR(哺乳類ラパマイシン標的)阻害剤である[参考文献]。mTORがラパマイシンにより阻害されると、ULKやベクリンなどのオートファジー関連主要因子が活性化され、それによりLC3の合成およびLC3−IIの変換が誘導され、オートファゴソーム生成の増加をもたらす(図20d)。オートファジー活性化剤としてのラパマイシンの効果ゆえに、治療剤としてのその価値は高い。しかしながら、mTORを介した広範囲な生物学的効果などの副作用のために治療剤としての使用は未だ限定されている。したがって、mTORを介さない新規オートファジー活性化剤の開発が緊急に必要とされている。
細胞内のミスフォールドタンパク質は、最初にユビキチン化の標的となり、次いでプロテアソームにより分解される。ミスフォールドタンパク質が凝集体化する条件下(例:変異ハンチントンタンパク質)では、プロテアソーム活性が減少しているか、またはミスフォールドタンパク質がプロテアソームに入ることができないため、ミスフォールドタンパク質はオートファジーにより集結され、ついでリソソームにより分解される。ZZリガンドがオートファジーフラックスを増加させる結果に基づき、ZZリガンドがユビキチン化された細胞内タンパク質のオートファジーへの輸送を増加させることができるかどうかを免疫染色により調べた。
ハンチントン病において観察されるハンチントンは、CAGコドンの過剰な繰り返し(少なくとも36リピート)のためにミスフォールドされやすいのみならず、凝集体(凝集塊)に迅速に変換されることから、タンパク質はユビキチン−プロテアソーム系により分解されないことが示唆される(図21a)。ラパマイシンを用いてオートファジーの活性化を誘導することによりそのような変異タンパク質を除去する技術が開発されたとしても、ラパマイシンは、mTORを介する様々な生物学的経路に影響を与えるため、治療剤としては適切でない。ZZリガンドがmTORを経ることなしにオートファジーを活性化することを考慮し、ZZリガンドがハンチントンタンパク質凝集体を除去することができるかどうかを調べた。
Claims (22)
- 神経変性疾患の抑制および処置のための医薬組成物であって、活性成分としてp62 ZZドメインに結合するリガンドを含む、前記組成物。
- p62タンパク質が配列番号1により表されるアミノ酸配列を含む、請求項1に記載の神経変性疾患の抑制および処置のための医薬組成物。
- ZZドメインが、配列番号1により表されるp62タンパク質のアミノ酸配列の128〜163残基を含有する、請求項1に記載の神経変性疾患の抑制および処置のための医薬組成物。
- リガンドが、Arg−Ala(配列番号2)、Phe−Ala(配列番号3)、Trp−Ala(配列番号4)、Tyr−Ala(配列番号5)、R−11(配列番号6)、W−11(配列番号7)、R−BiP(配列番号8)、およびR−BiPD(配列番号9)からなる群から選択される、請求項1に記載の神経変性疾患の抑制および処置のための医薬組成物。
- リガンドの活性成分が、Nt−Arg(式1)、Nt−Phe(式2)、Nt−Trp(式3)、およびNt−Tyr(式4)からなる群から選択されるN末端残基である、請求項4に記載の神経変性疾患の抑制および処置のための医薬組成物。
- リガンドが、p62−ZZ1(式5)またはp62−ZZ2(式6;NCI314953):
[式5]
- 神経変性疾患が、アルツハイマー病(AD)、パーキンソン病(PD)、ハンチントン病(HD)、プリオン病(PD)、多発性硬化症(MS)、ライムボレリア症、致死性家族性不眠症、クロイツフェルト・ヤコブ病(CJD)、認知症、てんかん、脳卒中、ピック病、および筋萎縮性側索硬化症(ALS;ルー・ゲーリック病)からなる群から選択される、請求項1に記載の神経変性疾患の抑制および処置のための医薬組成物。
- リガンドが、p62 ZZドメインに結合して、p62タンパク質のPB1ドメインおよびLlRドメインを活性化し、p62のオリゴマー化および凝集体形成の誘導をもたらす、請求項1に記載の神経変性疾患の抑制および処置のための医薬組成物。
- リガンドが、p62の凝集体形成を誘導することによりオートファゴソームを形成する、請求項1に記載の神経変性疾患の抑制および処置のための医薬組成物。
- 神経変性疾患の抑制および改善のための健康食品サプリメントであって、活性成分としてp62 ZZドメインに結合するリガンドを含む、前記健康食品サプリメント。
- リガンドが、Arg−Ala(配列番号2)、Phe−Ala(配列番号3)、Trp−Ala(配列番号4)、Tyr−Ala(配列番号5)、R−11(配列番号6)、W−11(配列番号7)、R−BiP(配列番号8)、およびR−BiPD(配列番号9)からなる群から選択される、請求項10に記載の神経変性疾患の抑制および改善のための健康食品サプリメント。
- リガンドの活性成分が、Nt−Arg(式1)、Nt−Phe(式2)、Nt−Trp(式3)、およびNt−Tyr(式4)からなる群から選択されるN末端残基である、請求項11に記載の神経変性疾患の抑制および改善のための健康食品サプリメント。
- リガンドが、p62−ZZ1(式5)またはp62−ZZ2(式6;NCI314953):
[式5]
- 神経変性疾患が、アルツハイマー病(AD)、パーキンソン病(PD)、ハンチントン病(HD)、プリオン病(PD)、多発性硬化症(MS)、ライムボレリア症、致死性家族性不眠症、クロイツフェルト・ヤコブ病(CJD)、認知症、てんかん、脳卒中、ピック病、および筋萎縮性側索硬化症(ALS;ルー・ゲーリック病)からなる群から選択される、請求項11に記載の神経変性疾患の抑制および改善のための健康食品サプリメント。
- リガンドが、p62 ZZドメインに結合して、p62のオリゴマー化を誘導し、次いでp62とLC3との間の結合を増加させることにより、p62の活性を増加させるための方法であって、p62 ZZドメインに結合するリガンドを、細胞またはp62タンパク質に対して処理するステップを含む、前記方法。
- p62 ZZドメインにリガンドを結合させることによりオートファゴソームへの662の輸送を増加させる方法であって、p62 ZZドメインまたはp62タンパク質に結合するリガンドで細胞を処理するステップを含む、前記方法。
- p62 ZZドメインにリガンドを結合させることによりオートファジーを活性化させる方法であって、p62 ZZドメインまたはp62タンパク質に結合するリガンドで細胞を処理するステップを含む、前記方法。
- p62 ZZドメインにリガンドを結合させることによりオートファゴソームへミスフォールドタンパク質凝集体を移行させるプロセスを活性化させる方法であって、p62 ZZドメインまたはp62タンパク質に結合するリガンドで細胞を処理するステップを含む、前記方法。
- p62 ZZドメインにリガンドを結合させることにより、オートファジーの活性化を介してリソソームによるミスフォールドタンパク質凝集体の分解を促進させる方法であって、p62 ZZドメインまたはp62タンパク質に結合するリガンドで細胞を処理するステップを含む、前記方法。
- 神経変性疾患を抑制および処置するための方法であって、p62 ZZドメインに結合するリガンドを対象において投与するステップを含む、前記方法。
- 神経変性疾患の抑制および処置のための組成物ための、p62 ZZドメインに結合するリガンドの使用。
- 神経変性疾患の抑制および改善のための健康食品サプリメントのための、p62 ZZドメインに結合するリガンドの使用。
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