JP2023081919A - チューブリンカルボキシペプチダーゼ関連疾患を処置するための方法及び医薬組成物 - Google Patents
チューブリンカルボキシペプチダーゼ関連疾患を処置するための方法及び医薬組成物 Download PDFInfo
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Abstract
Description
本発明は、バソヒビン又はバソヒビン/SVBP(低分子バソヒビン結合タンパク質)複合体の活性又は発現の阻害剤を用いて、チューブリンカルボキシペプチダーゼ(TCP)関連疾患、例えば神経学的障害及び心血管疾患を処置するための方法及び医薬組成物に関する。
微小管は、細胞分裂、運動性及び形態形成に中心的に関与するα/βチューブリンダイマーの細胞骨格ポリマーである。チューブリンの脱チロシン化/チロシン化サイクルでは、α-チューブリンのC末端チロシンは、理解困難なペプチダーゼ(TCP)によって除去され、チューブリンチロシンリガーゼ(TTL、総説については、((Barra et al. (1988), Mol Neurobiol, 2:133)1)を参照のこと)によって再付加される。チューブリンにユニークであり、脊索動物から哺乳動物への進化の間でほとんど保存されているこのサイクルは、in vivoで重要な役割を有する((Erck et al. (2005), Proc Natl Acad Sci U S A, 102:7853)2)。α-チューブリンのチューブリン脱/チロシン化は、有糸分裂(Badin-Larcon et al. (2004), Proc Natl Acad Sci U S A, 101:5577; Barisic and Maiato (2016), Trends Cell Biol; Barisic et al. (2015), Science, 348:799) (Barisic and Maiato, 2016; Barisic et al., 2015)(3~5)(Gobrecht et al. (2016), Journal of Neuroscience 36.14: 3890-3902.; Konishi and Setou (2009), Nat Neurosci, 12:559; Marcos et al. (2009), PloS one, 4:e5405; Peris et al. (2006), J Cell Biol, 174:839-849)、神経生理学(6~8)及び筋肉メカノトランスダクション(Kerr et al. (2015), Nature communications, 6:8526; Robison et al. (2016), Science, 352:aaf0659)(9、10)の重要な調節シグナルであるその結果として、異常なチロシン化レベルは、細胞トランスフォーメーション及び腫瘍浸潤性(Lafanechere et al. (1998), J Cell Sci, 111 ( Pt 2):171; Whipple et al. (2007), Exp Cell Res, 313:1326)(11、12)、神経崩壊(Erck et al. (2005), Proc Natl Acad Sci U S A, 102:7853; Peris et al. (2006), J Cell Biol, 174:839; Peris et al. (2009), J Cell Biol, 185:1159)(2)並びに心不全及び心筋症(Robison et al. (2016), Science, 352:aaf0659)(10、13)に関連する脱チロシン化反応は40年前に最初に記載されたが(14)、TCPの正体は依然として不明であるので、前記サイクルの完全な理解は依然として不足している。
α-チューブリンの可逆的脱チロシン化は微小管ダイナミクス及び機能に重要であり、その欠陥は、ガン、脳崩壊及び心筋症に関与している。しかしながら、脱チロシン化を担当するチューブリンチロシンカルボキシペプチダーゼ(TCP)の同定は依然として未成功である。本明細書では、強力でユニークな不可逆的な阻害剤と共に化学プロテオミクスを使用して、本発明者らは、主要な脳TCPがバソヒビン-1(VASH1)と低分子バソヒビン結合タンパク質(SVBP)との複合体であることを見出した。VASH1及びそのホモログバソヒビン-2(VASH2)は、SVBPと複合体形成すると、微小管に対するロバストかつ特異的なTyr/Pheカルボキシペプチダーゼ活性を示す。したがって、本発明者らは、バソヒビン及びバソヒビン/SVBP複合体の酵素活性を最初に実証した。培養ニューロンにおけるバソヒビン又はSVBPのノックダウンは、チロシン化α-チューブリンレベルの顕著な減少及び重度の分化欠陥の発症をもたらす。更に、バソヒビンのノックダウンは、発達中のマウス新皮質のニューロン移動を破壊する。これらの結果は、バソヒビン/SVBP複合体がTCP酵素であることを立証している。
「バソヒビン活性の阻害剤」又は「バソヒビン/SVBP複合体活性の阻害剤」は、当技術分野におけるその同じ一般的な意味を有し、バソヒビン(又はその複合体)又はそのメンバーの1つの生物学的活性を減少させ又は抑制する能力を有する化合物(天然又は非天然)を指す。典型的には、前記化合物は、バソヒビン(又はその複合体)によるチューブリンの脱チロシン化を阻害し又は減少させる。例えば、化合物は、基質に代わって触媒部位に入り得るか、又はバソヒビン(又はその複合体)とチューブリン/微小管/微小管関連タンパク質、例えば+Tip(プラス-エンドトラッキングタンパク質)との相互作用を遮断し得るか、又はバソヒビンがチューブリン/微小管/微小管関連タンパク質、例えば+Tipに結合することができない様式でバソヒビン(又はその複合体)に結合し得るか、又はバソヒビン/SVBP複合体の形成を阻害し得る。典型的には、前記阻害剤は、有機小分子又は生体分子(例えば、ペプチド、脂質、抗体、アプタマー)である。
●VASH1については:Saito M et al. The Journal of Biochemistry, 160(4), Oct. 2016, p.227-232); (Watanabe, K., et al. (2004). J. Clin. Invest. 114, 898907)及び抗バソヒビン1/VASH1抗体(C末端) IHC-plus(商標)LS-B9515 (Lifespan Bioscience)
●VASH2については:Koyanagi T. et al Cancer Sci. 2017 Mar;108(3):512-519);米国特許第9701744号及び抗VASH2治療用抗体(1760) TAB-248CQ (creative biolab)、抗VASH2(H00079805-H01) Novus bio.
●SVBPについては、抗SVBP抗体(HPA008507 SIGMA)
「バソヒビン発現の阻害剤」又は「バソヒビン/SVBP複合体発現の阻害剤」は、バソヒビンの少なくとも1つの異なるメンバー(又はその複合体)をコードする少なくとも1つの遺伝子の発現を阻害し又は有意に減少させる生物学的効果を有する天然又は合成化合物を指す。
●バソヒビン1については、Kitajima T., et al Anticancer Research October 2014 vol. 34(10) p.5321-5329; Miyashita H, et al (2012). PLoS ONE 7(10): e46459; Watatani H et al, Physiol Rep. 2014 June; 2(6): e12054.Vasohibin-1 Gene Silencers siRNA (h), sc-61776, (SantaCruz Biotechnology); SMARTpool: Accell VASH1 siRNA (Darmacon) ; Invitrogen Stealth mouse siRNA MSS280250、MSS280251及びMSS280252.
●バソヒビン2については:Tu, M., et al (2016). (Cancer Letters; 383(2), 28 Dec. ; p. 272-281) ; Koyanagi T. et al (Cancer Science 104(12) Dec. 2013 p.1705-1710) ; Suenaga K. et al (PLoS One. 2014; 9(9): e104728) ; Invitrogen Stealth mouse siRNA MSS213191、MSS280251及びMSS280252.
●SVBPについては、Suzuki Y, et al (J Cell Sci 2010 123: 3094-3101).
●バソヒビン-1:CCGAGACATGCGGCTCAAGATTGGCAAGG(配列番号1)
●バソヒビン-2:AGACAAATCGCCTGCTCTGACCGAGAAGA(配列番号2)
●SVBP:AGAGTGGAGAAGGCTAAGCAGAAATCTGC(配列番号3)
バソヒビン/SVBP複合体活性又は発現の阻害剤を、薬学的に許容し得る賦形剤及び場合により持続放出マトリックス、例えば生分解性ポリマーと組み合わせて、治療用組成物を形成し得る。
本発明は更に、候補バソヒビン/SVBP複合阻害剤(「TCP阻害剤」とも称される)をスクリーニングするための方法に関する。本発明の方法は、
(i)候補化合物を、バソヒビン/SVBP(TCP)及びビオチニル-V-D-S-V-E-G-E-G-E-E-E-D-E-E-Y(配列番号13)の配列のビオチン化ペプチドと共にインキュベーションする工程;
(ii)質量分析により、工程(i)の終了時に得られた混合物中に存在するビオチニル-V-D-S-V-E-G-E-G-E-E-E-D-E-E-Y(配列番号13)のビオチン化ペプチド及び/又はビオチニル-V-D-S-V-E-G-E-G-E-E-E-D-E-Eのビオチン化ペプチドを定量する工程;並びに
(iii)工程(ii)で得られた結果を考慮して、前記候補化合物がTCP阻害剤であるかを決定する工程
を含む。
材料及び方法:
動物。雄又は雌マウスを2~4カ月齢で使用した。Institut des Neurosciences of Grenoble (GIN)のポリシー及びフランスの法律にしたがって、1986年11月24日の欧州共同体理事会指令(86/609/EEC)に準拠して実験を行った。動物に関わる調査は、Direction Departementale de la protection des populations-Prefecture de l’Isere-Franceによって、及びフランス調査省が認定したGIN番号004の倫理委員会によって承認された。
TCPを濃縮するために、基質としてタキソール安定化放射性標識チロシン化微小管を使用して活性を追跡する3段階精製手順を設計した。典型的な手順では、ほぼ400倍の最終精製係数が得られた(図1A)。最後の画分(IV)は、微小管に組み込まれたチューブリンからC末端チロシンを切断することができたが、EB1からは切断することができなかった。EB1は、α-チューブリンと類似のC末端配列(-GEEYに代えてQEEY)を共有するタンパク質であり、一般的に、生理学的状況ではTCPの基質ではない(15)。
1 論理的根拠。
アルツハイマー病患者及びコントロール患者の脳のイムノブロッティングによって、チロシン化、脱チロシン化及びΔ2-チューブリン(別の形態の脱チロシン化チューブリン)の量を分析した。病理学の異なるBraak段階でそれらを分析し、健常脳の対応するコントロールサンプルと比較した。各サンプルについて、脳領域 4つ(内嗅皮質、海馬、側頭及び前頭皮質)を分析した。
組織。ヒト組織サンプルは、52~93歳の男性及び女性患者 29人のパネルからの脳領域 4つ(内嗅皮質、海馬、側頭皮質、外側前頭前皮質)からなる。コントロール 11個、Braak段階I~II 5個、Braak段階III~IV 6個及びBraak段階IV~V 7個(詳細については、添付1を参照のこと)。
患者 29人の領域 4つのサンプルは、分析すべきサンプル 116個になる。各サンプルを3回反復で分析した。RIPA上清(凍結サンプルの1/4希釈物 10μl)を無染色4%-15%ゲル(Bio Rad)の電気泳動に供し、次いで、Trans-Blot Turbo Transfer System (Bio Rad)を使用してニトロセルロース膜に迅速に転写した。脱チロシン化及びΔ2チューブリンに対する特異的抗体を1/20000で使用して、ブロットを明らかにした。ポリクローナルα3A1抗体を1/10000希釈で使用して、総α-チューブリンを検出した。適切なペルオキシダーゼ標識二次抗体を1/20000で使用した。Pierce ECLウエスタンブロッティング基質(Thermo scientific)を使用してブロットを明らかにし、定量のためにImage Labソフトウェアを使用してChemiDoc(商標)MPイメージングシステム(Bio Rad)を用いて分析した。
結果は図8に示されている。
材料及び方法:
生化学分析のための脳組織の調製:
Precellys装置ホモジナイザー(2×20秒間、5000rpm)を使用して、150mg/mLのプロテアーゼ(P8340, Sigma)及びホスファターゼ阻害剤カクテル(P5726 and P0044, Sigma)を補充した溶解バッファー(CaCl2及びMgCl2を含まないリン酸緩衝生理食塩水(PBS)、14190-094 Life Technologies)中で、海馬をホモジナイズした。次いで、溶解物を21,000g、4℃で20分間遠心分離した。得られた上清を収集し、ビシンコニン酸アッセイ(Pierce/Thermo Fisher Scientific)を使用してタンパク質濃度を決定した。サンプルを分析まで-80℃で保存した。
SVBP、VASH1及びVASH2 KO野生型、ヘテロ接合性及びホモ接合性マウス由来の海馬の溶解物において、自動Simple Western system (Protein Simple)を使用して、チロシン化、脱チロシン化、デルタ2チューブリン、総α-チューブリン及びチューブリンチロシンリガーゼレベルを評価した。ユーザーマニュアルにしたがって、表1に記載されている一次抗体以外は製造業者の試薬を用いて、全ての手順を実施した。サンプルをタンパク質濃度 0.125μg/μLでロードし、一次抗体と共に60分間インキュベーションし、二次抗マウス又は抗ウサギIgGと共に30分間インキュベーションした。Compassソフトウェア(Protein Simple)を用いて、データを分析した。GAPDHレベルに対して、タンパク質レベルを正規化した。
プロテアーゼ(Roche; 04906837001)及びホスファターゼ阻害剤(Roche; 11836153001)の存在下で、タンパク質抽出バッファー(Cellsignaling; 9803S)中、ウエスタンブロット用FastPrepホモジナイザーを用いて、Precellysチューブ(KT03961-1-007.2)中で、心室由来のタンパク質(約50mg)をホモジナイズした。12%ビストリスSDS-ポリアクリルアミドゲル電気泳動(Bio-Rad; 3450119)で等量のタンパク質(30μg)を分離し、TransBlotシステム(Bio-Rad;170-4159)を用いてニトロセルロース膜に転写した。GAPDH(1/10000、Millipore; MAB374)、α-チューブリン(1/5000、Sigma; T6199-200μgL)、チロシン化チューブリン(1/1000、Abcam; ab6160)、脱チロシン化チューブリン(1/1000、Abcam; ab48389)、デルタ2-チューブリン(1/1000、Abcam; ab106658)に対する一次抗体、続いて、赤外線色素コンジュゲート二次抗体(1/1000~1/10000、Li-Cor)を用いて、タンパク質を検出した。Odysseyスキャナーを使用してデンシトメトリー分析によってタンパク質の定量を達成し、Gapdhレベルに対して正規化した。
微小管の脱チロシン化に対するバソヒビン1、バソヒビン2及びSVBPの機能をin vivoで確認するために、本発明者らは、バソヒビン1、バソヒビン2又はSVBPタンパク質のいずれかに関するノックダウントランスジェニックマウス(野生型、ヘテロ接合性及びホモ接合性)におけるチロシン化チューブリン、脱チロシン化チューブリン、デルタ2チューブリン、総α-チューブリン及びチューブリンチロシンリガーゼレベルを測定したGrenoble Institute for Neuroscienceにおいてで作成されたマウス由来の脳(海馬)及び心臓(心室)に対して、この研究を実施した。
1 論理的根拠。
本発明者らの仮説は、脱チロシン化微小管の蓄積がシナプス可塑性に有害であり、ADの初期段階に特徴的な樹状突起スパイン及びシナプス喪失に寄与し得る微小管ダイナミクスの喪失につながり得るというものである。
マウス。CRISPR/Cas9遺伝子編集によって、マウスにおいてSVBP、VASH1及びVASH2ノックアウトを生成した(VASH1 KOの生成については、Teixera et al 2018を参照のこと)。SVBPについてはエクソン2中の配列をターゲティングし、Vash1についてはエクソン1中の配列をターゲティングし、Vash2についてはエクソン2中の配列をターゲティングした。マイクロインジェクション胚の再移植後に誕生したF0モザイク動物を、PCR/サンガーシーケンシングによって遺伝子型決定し、次いで、C57BL/6マウスと交配して、少なくともF4/F5マウスを得た。
結果は図15及び16に示されている。
1-論理的根拠:
後根神経節(DRG)に位置する細胞体を有するニューロンは偽単極性であり、2つの軸索(傷害時に再生することができる末梢軸索、及び中枢神経系に入る中枢軸索であって、傷害後に再生することができない中枢軸索)に分枝する単一の軸索を有する。末梢軸索の傷害は、中枢枝における再生プロセス(分子、細胞)にもつながることが示されているが、これは、対応する末梢軸索も傷害される場合には、これらのDRGニューロンの中枢軸索が再生することができることを意味する(Richardson and Verge, 1987)。この効果は、コンディショニング病変効果又はプレコンディショニングと称される。病変のコンディショニングは、ニューロンにおける固有の再生能力の増強を誘導し、神経突起成長の増強につながる(Smith and Skene, 1997)。
左坐骨神経を30秒間鉗子破砕することによって、成体(2月齢)WT及びSVBP KO成体マウスを外科的にコンディショニングした(プレコンディショニング条件)。3日後、次いで、坐骨神経を形成するものに対応するDRGのニューロンを培養し、対側DRGニューロン(コントロール条件)と比較した。
結果は図17に示されている。
1 論理的根拠。
TCP又はVASH/SVBP複合体は、微小管上のαチューブリンのC末端チロシン又はチューブリンの遊離ダイマーを切断する酵素である(Aillaud et al., 2017)。本発明者らは、αチューブリンのC末端配列に対応するペプチドを脱チロシン化するそれらの能力、及びこの活性に対するいくつかの潜在的な阻害剤の効果を試験した。このようなアッセイは、大規模な薬物セットのスクリーニングに適合させ得る。
VASH/SVBP複合体の脱チロシン化活性を検出及び定量するために、プレートベースのアッセイ技術を設計した。簡潔に言えば、リン酸緩衝生理食塩水(PBS)中50μg/mlのニュートラアビジンでコーティングした96ウェルImmulon 4HBXプレート上で、アッセイを実施した。PBS中0.05%Tweenでリンスした後、ビオチニル-V-15-Yペプチド(ビオチニル-Val-Asp-Ser-Val-Glu-Gly-Glu-Gly-Glu-Glu-Glu-Gly-Glu-Glu-Tyr)をPBS中10-8Mでプレート上にコーティングし、続いて、PBS中Tween0.05%でリンスした。次いで、様々な濃度のDMSO又は阻害剤と共に0℃で2時間プレインキュベーションしたVASH1/SVBP酵素(0.2μM)を30分間の反応でペプチドに添加した。PBS中0.05%Tweenで3回リンスすることによって、反応を停止させた。次いで、一次抗体として抗チロシン化チューブリン(YL1/2、1/2000)、二次抗体として抗ラットHRP(1/5000)を使用し、ELISA用HRP基質としてTMB溶液(Sigma)を用いて、PHERAstarシステム(BMG Labtech)によって、免疫検出を実施した。
結果は図18に示されている。
RapidFire(登録商標)/質量分析(MS)によるチューブリンカルボキシペプチダーゼ(TCP)又はチューブリンチロシンリガーゼ(TTL)の研究は、他の既存のアッセイフォーマットに対して多数の利点を提供する。第1に、システムは、放射性基質を使用する場合に必要とされるコスト及び特別な取扱手順を回避する。第2に、RapidFire(登録商標)/MSベースのアッセイは、データの解釈を複雑化し得る二次反応又は共役反応を伴わない。第3に、MSによってペプチド種を直接測定するので、データのアーチファクトを引き起こし得る蛍光タグが必要ない。
RapidFire(登録商標)365(Agilent Technology)ハイスループットシステム(RF)を、エレクトロスプレー負イオンモードで操作されるG-6460トリプル四重極質量分析計(Agilent)に接続した。タイプCカートリッジをサンプルの捕捉及び溶出に使用した。RapidFire(登録商標)法は、MS検出に直接結合した固相抽出(SPE)サンプルクリーンアップ工程を用いる。
Claims (15)
- それを必要とする被験体におけるチューブリンカルボキシペプチダーゼ(TCP)関連疾患を処置するための方法において使用するための、バソヒビン又はバソヒビン/SVBP(低分子バソヒビン結合タンパク質)複合体活性又は発現の阻害剤。
- 前記チューブリンカルボキシペプチダーゼ関連疾患が神経学的障害である、請求項1に記載の使用のための阻害剤。
- 前記神経学的障害が、多発性硬化症、脳卒中、筋萎縮性側索硬化症、パーキンソン病、ハンチントン病及びアルツハイマー病からなる群より選択される神経変性障害である、請求項2に記載の使用のための阻害剤。
- 前記神経変性障害がアルツハイマー病である、請求項3に記載の使用のための阻害剤。
- 前記チューブリンカルボキシペプチダーゼ関連疾患が、心筋梗塞、心筋梗塞誘発性心血管機能障害、心不全、心筋症及びジストロフィン異常症からなるリストより選択される心血管疾患である、請求項1に記載の使用のための阻害剤。
- 前記心血管疾患が心筋症である、請求項5に記載の使用のための阻害剤。
- バソヒビン活性の前記阻害剤が有機小分子又は生体分子である、請求項1~6のいずれか一項に記載の使用のための阻害剤。
- バソヒビン活性の前記阻害剤が、バソヒビン-1又はバソヒビン-2の活性の阻害剤からなるリストより選択される、請求項7に記載の使用のための阻害剤。
- バソヒビン発現又はバソヒビン/SVBP複合体発現の前記阻害剤が、アンチセンスオリゴヌクレオチド、siRNA、shRNA及びリボザイムからなるリストより選択される、請求項1~6のいずれか一項に記載の使用のための阻害剤。
- バソヒビン/SVBP複合体発現の前記阻害剤が、バソヒビン-1 バソヒビン-2又はSVBPの発現の阻害剤からなるリストより選択される、請求項9に記載の使用のための阻害剤。
- それを必要とする被験体におけるチューブリンカルボキシペプチダーゼ(TCP)関連疾患を処置するための方法において使用するための医薬組成物であって、請求項1~10のいずれかに記載のバソヒビン又はバソヒビン/SVBP複合体活性又は発現の阻害剤を含む、医薬組成物。
- 前記チューブリンカルボキシペプチダーゼ関連疾患が、神経学的障害及び心血管疾患からなるリストより選択される、請求項11に記載の使用のための医薬組成物。
- チューブリンカルボキシペプチダーゼ(TCP)関連疾患を処置するために有用な複数の候補化合物をスクリーニングするための方法であって、(a)バソヒビン又はバソヒビン/SVBP複合体活性又は発現を阻害するその能力について、該候補化合物の各々を試験すること、及び(b)及び該バソヒビン又はバソヒビン/SVBP複合体活性又は発現を阻害することができる候補化合物をポジティブ選択することからなる工程を含む、方法。
- 候補チューブリンカルボキシペプチダーゼ(TCP)阻害剤をスクリーニングするための方法であって、(i)試験すべき候補化合物を、TCP及びビオチニル-V-D-S-V-E-G-E-G-E-E-E-D-E-E-Y(配列番号13)の配列のビオチン化ペプチドと共にインキュベーションする工程;質量分析によって、工程(i)の終了時に得られた混合物中に存在するビオチニル-V-D-S-V-E-G-E-G-E-E-E-D-E-E-Y(配列番号13)のビオチン化ペプチド及び/又はビオチニル-V-D-S-V-E-G-E-G-E-E-E-D-E-Eのビオチン化ペプチドを定量する工程;並びに(iii)工程(ii)で得られた結果を考慮して、前記候補化合物がTCP阻害剤であるかを決定する工程を含む、方法。
- 工程(iii)で定量するために、工程(i)及び(ii)の間に、ビオチニル-V-D-S-V-E-G-E-G-E-E-E-D-E-E(配列番号12)及び/又はビオチニル-V-D-S-V-E-G-E-G-E-E-E-D-E-E-Y(配列番号13)のビオチン化ペプチド(単数又は複数)を単離する精製工程を更に含む、請求項14に記載の方法。
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