JP6300856B2 - ゼブラフィッシュモデルを用いることにより薬物をスクリーニングする方法、及びこの方法によりスクリーニングされた化合物 - Google Patents
ゼブラフィッシュモデルを用いることにより薬物をスクリーニングする方法、及びこの方法によりスクリーニングされた化合物 Download PDFInfo
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- JP6300856B2 JP6300856B2 JP2016077013A JP2016077013A JP6300856B2 JP 6300856 B2 JP6300856 B2 JP 6300856B2 JP 2016077013 A JP2016077013 A JP 2016077013A JP 2016077013 A JP2016077013 A JP 2016077013A JP 6300856 B2 JP6300856 B2 JP 6300856B2
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Description
本発明は、ゼブラフィッシュをモデルとして用いて、薬物をスクリーニングする方法に関する。特に、本発明は、ルミカン(Lumican)の発現及びコラーゲン原線維形成(collagen fibrillogenesis)に影響を与え、ルミカンの発現及び/又はコラーゲン原線維形成により調節される疾患を治療するための候補化合物を同定する方法、及びこの方法により同定された候補化合物に関する。さらに、この方法により、近視及び/又は円錐角膜(keratoconus)疾患を治療及び/又は予防するための薬物を同定する。
(a)ゼブラフィッシュの複数の受精胚に、ルミカン遺伝子及び/又はコラーゲン原線維形成関連遺伝子のアンチセンスmRNA、または前記アンチセンスmRNAのアナログを導入すること、
(b)前記(a)で得られたゼブラフィッシュが、十分な長さの時間で試験化合物に暴露された後、ゼブラフィッシュを集めること、及び
(c)ゼブラフィッシュの大きな眼の数を計測し、前記ゼブラフィッシュの大きな眼の割合が低下した場合、前記試験化合物を候補化合物と定義すること。
(a)ゼブラフィッシュの複数の受精胚に、ルミカン遺伝子及び/又はコラーゲン原線維形成関連遺伝子のアンチセンスmRNA、または前記アンチセンスmRNAのアナログを導入すること、
(b)前記(a)で得られたゼブラフィッシュが、十分な長さの時間で試験化合物に暴露された後、ゼブラフィッシュを集めること、及び
(c)ゼブラフィッシュの大きな眼の数を計測し、ゼブラフィッシュの眼の総数または試験化合物で処理されていない対照群のゼブラフィッシュの大きな眼の総数に対して、ゼブラフィッシュの大きな眼の割合が低下した場合、前記試験化合物を候補化合物と定義すること。
(a)ゼブラフィッシュの複数の受精胚に、ルミカン遺伝子及び/又はコラーゲン原線維形成関連遺伝子のアンチセンスmRNA、または前記アンチセンスmRNAのアナログを導入すること、
(b)前記(a)で得られたゼブラフィッシュが、十分な長さの時間で試験化合物に暴露された後、ゼブラフィッシュを集めること、及び
(c)ゼブラフィッシュの大きな眼の数を計測し、前記ゼブラフィッシュの大きな眼の割合が低下した場合、前記試験化合物を候補化合物と定義すること。
(a)ゼブラフィッシュの複数の受精胚に、ルミカン遺伝子及び/又はコラーゲン原線維形成関連遺伝子のアンチセンスmRNA、または前記アンチセンスmRNAのアナログを導入すること、
(b)前記(a)で得られたゼブラフィッシュが、十分な長さの時間で試験化合物に暴露された後、ゼブラフィッシュを集めること、及び
(c)ゼブラフィッシュの大きな眼の数を計測し、ゼブラフィッシュの眼の総数または試験化合物で処理されていない対照群のゼブラフィッシュの大きな眼の総数に対して、ゼブラフィッシュの大きな眼の割合が低下した場合、前記試験化合物を候補化合物と定義すること。
<ゼブラフィッシュのケラトカン及びルミカンの遺伝子>
<ノックダウンゼブラフィッシュ>
<ノックダウンゼブラフィッシュが試験化合物に暴露されること、及び結果としてのゼブラフィッシュを集めること>
<ゼブラフィッシュの大きな眼の計測、及び候補化合物の同定>
本発明の新規なスクリーニング方法は、ルミカンノックダウンゼブラフィッシュの大きな眼の割合を低下させる化合物の同定に用いられる。この同定された化合物としては、例えば、有機のまたは無機の小分子(分子量が1,000Da未満のもの)、オリゴペプチド、オリゴヌクレオチド、または炭水化物などが挙げられる。「試験化合物」とは、任意の化合物であってもよく、例えば、高分子(ポリペプチド、タンパク質複合体、糖タンパク質、または核酸)または小分子(アミノ酸、ヌクレオチド、有機化合物または無機化合物)が挙げられる。前記試験化合物は、10,000g/mol未満の式量、5,000g/mol未満の式量、1,000g/mol未満の式量、または500g/mol未満の式量を有してもよい。前記試験化合物は、自然発生的なもの(例えば、ハーブまたは天然物)、人工的に合成されたもの、または自然発生的なものと人工的に合成されたものとを含むものであってもよい。試験化合物の例は、メタロプロテアーゼ阻害剤、コラゲナーゼ阻害剤、TGF−β経路活性剤、TGF−β阻害剤及びCox阻害剤を含む。
<ルミカンの発現及び/又はコラーゲン原線維形成に影響を与える、及び/又は近視及び/又は円錐角膜疾患を治療する方法における、メタロプロテアーゼ阻害剤の使用>
メタロプロテアーゼ(MMPs)は、細胞増殖、移動(接着・分散)、分化、血管形成、アポトーシス及び宿主防御などの細胞行動に、重要な役割を担うとも思われる。メタロプロテアーゼ阻害剤は、従来知られている。生化学的物質を含む例としては、メタロプロテアーゼの組織阻害剤(TIMPs)、α2−マクログロブリン及びそれらのアナログ又は誘導体が挙げられる。多数の小さいペプチド様化合物が、メタロプロテアーゼを阻害することは既に記述されている。チオール基を有するアミド又はペプチジルアミドに基づくメタロプロテアーゼ(MMP)阻害剤は、例えば、W095/12389、WO96/11209及び米国特許第4,595,700号に記載される。ヒドロキサメート基を有するMMP阻害剤は、多数の公開された特許文献、例えば、炭素骨格化合物が開示されたWO95/29892、WO97/24117、WO97/49679及びEP0780386、及び、ペプチジル骨格又はペプチド模倣骨格を有するヒドロキサメートが開示されたWO90/05719、WO93/20047、WO95/09841及びWO96/06074において、開示されている。また、他のピリミジン系MMP阻害剤、ヒドロキシピロン系MMP阻害剤、リン系MMP阻害剤及びテトラサイクリン系MMP阻害剤も報告されている(Cancer Metastasis Rev., 2006, 25:115−136を参照のこと)。
その中、Qは、存在しない、または
Xは、C1−10アルキレン基、C2−10アルケニレン基又はC2−10アルキニレン基であり、これらは非置換のもの、あるいは1個以上のOH、直鎖状のもしくは分枝鎖状のC1−10アルキル基、直鎖状のもしくは分枝鎖状のC2−10アルケニル基、C1−10アルキルC5−15アリール基、C1−10アルケニルC5−15アリール基、C1−10アルキニルC5−15アリール基、C1−10アルキルスルファニルC5−15アリール基、C1−10アルキルスルホニルC5−15アリール基、C1−10アルキルスルフィニルC5−15アリール基、C1−10アルキルオキシ基またはC5−15アリール基で置換されたものである。
Yは、C1−10アルキレン基、C2−10アルケニレン基又はC2−10アルキニレン基であり、それらは、非置換のもの、あるいは1個以上のOH、直鎖状のもしくは分枝鎖状のC1−10アルキル基、直鎖状のもしくは分枝鎖状のC2−10アルケニル基、C1−10アルキルC5−15アリール基、C1−10アルケニルC5−15アリール基、C1−10アルキニルC5−15アリール基、C1−10アルキルスルファニルC5−15アリール基、C1−10アルキルスルホニルC5−15アリール基、C1−10アルキルスルフィニルC5−15アリール基、C1−10アルキルオキシ基、C5−15アリール基、C1−10アルキルC5−15アリール基、C5−14ヘテロアリール基、C1−10アルキルC5−14ヘテロアリール基、またはC1−10アルキルスルファニルC5−14ヘテロアリール基で置換されたものである。但し、前記Qが存在しない場合、YはC5−14ヘテロアリール基である。このヘテロアリール基は、任意に置換されたものであり、N、O及びSから独立に選ばれる1〜3個のヘテロ原子を有するものである。
R1は、H、OH、C1−10アルキル基、C2−10アルケニル基、C2−10アルキニル基、C5−15アリール基、C1−10アルキルC5−15アリール基、C5−14ヘテロアリール基、またはC1−10アルキルC5−14ヘテロアリール基である。
その中、R1及びR6は、それぞれ独立に、H、C1−10アルキルC5−14ヘテロアリール基、又はC1−10NR7R8を表す。
R2は、水素原子又はOHである。
R3及びR4は、それぞれ独立に、H、OH、NH2、NO、CN、C1−10アルキル基、C1−10アルケニル基又はC1−10アルキニル基を表す。
R5は、水素原子、ハロゲン原子、NH2、OH、NO、CN、C1−10アルキル基、NHC1−10アルキル基、N(C1−10アルキル)2基、C5−15アリール基又はC5−14ヘテロアリール基である。
R7及びR8は、それぞれ独立に、H、C1−10アルキルC1−10アルキルNH2COOHであるか、又はそれぞれが結合している窒素原子と一緒に3〜8員のヘテロアリール基を形成する。
その中、前記ヘテロアリール基は、N、O及びSから独立に選ばれる1〜3個のヘテロ原子を有する。
その中、
R1は、ハロゲン原子、OH、NH2、OC1−10アルキル基であり、これらは非置換のもの、又は1〜3個のハロゲン原子もしくはNH2で置換されたものである。
Qは、存在しない、又はOである。
Xは、O又はS(O)2である。
Yは、CH2又はNHである。
Zは、N、O及びSから独立に選ばれる1〜3個のヘテロ原子を有するC5−14ヘテロアリール基、又は
R2、R3及びR4は、それぞれ独立に、H、C1−10アルキル基、
<ルミカンの発現及び/又はコラーゲン原線維形成に影響を与える、及び/又は近視及び/又は円錐角膜疾患を治療する方法における、TGF−β阻害剤の使用>
<ルミカンの発現及び/又はコラーゲン原線維形成に影響を与える、及び/又は近視及び/又は円錐角膜疾患を治療する方法における、COX/LOX阻害剤の使用>
<ルミカンの発現及び/又はコラーゲン原線維形成に影響を与える、及び/又は近視及び/又は円錐角膜疾患を治療する方法における、抗コリン性又はムスカリン性化合物の使用>
好ましい脂肪酸およびエステルは、アラキドン酸、オレイン酸、エイコサン酸、ラウリン酸、カプリル酸、カプリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、リノール酸、リノレン酸、ジカプラート、トリカプラート、モノオレイン、ジラウリン、グリセリル1−モノカプラート、1−ドデシルアザシクロヘプタン−2−オン、アシルカルニチン、アシルコリンもしくはC1−10 アルキルエステル(例えば、イソプロピルミリステート、IPM)、モノグリセリド、ジグリセリド又はそれらの医薬的に許容される塩を含むが、これらに限定されていない。
<水産養殖>
ゼブラフィッシュを、従来構築されたプロトコルに従って飼育及び維持した(Soules KA, Link BA. Morphogenesis of the anterior segment in the zebrafish eye. BMC Dev Biol 2005;5:12を参照のこと)。すべての実験は、28℃で14時間照光及び10時間暗闇のサイクルで育てられ、標準方法で維持されたテュービンゲンABゼブラフィッシュ(Tuebingen AB zebrafish)を用いて行われた。胚を、形態学的基準(体節数)に従って段階分けして(Kimmel CB, Ballard WW, Kimmel SR, et al. Stages of embryonic development of the zebrafish. Dev Dyn 1995;203(3):253−310を参照のこと)、受精後の時間数で時間を計る。ゼブラフィッシュのハンドブック(Westerfield M. The zebrafish Book; A Guide for the Laboratory Use of zebrafish (Brachydanio rerio). University of Oregon Press, Eugene,2nd edition 300P.,1993を参照のこと)に記載されたように、胚は、自然な対交配により生じた。交配ごとに4±5対と設定し、対ごとに平均に100±150個の胚が生じた。ゼブラフィッシュの胚が、光学的に透明なものであるため、殺処分または解剖する必要がなく、内臓器官の機能的及び形態学的な変化を観察することが可能となる。絨毛膜を、手動によりDumont Watchmaker’s Forceps No.5で除去した。
<ゼブラフィッシュのルミカンのクローン>
第1のルミカン特異的プライマー:5’−AGTAGAGGTATTTGATTCCGGTC−3’;
第2のルミカン特異的プライマー:5’−GCACAAGAAGGTGATGAAACG−3’;
第3のルミカン特異的プライマー:5’−CAGACTTAGAAGTCCAGCCAAC−3’;
第4の遺伝子特異的プライマー:5’−GCCTCAGAGATCATCTTTGAATAG−3’;
アブリッジドアンカープライマー:5’−GGCCACGCGTCGACTAGTACGGGIIGGGIIGGGIIG−3’;
汎用の増幅プライマー:5’−CUACUACUACUAGGCCACGCGTCGACTAGTAC−3’.
<モルフォリノノックダウン>
<全胚in situハイブリダイゼーション>
<抗体>
<ウエスタンブロット法>
一次抗体反応の後、二次抗体としての西洋ワサビペルオキシダーゼが接合されたヤギ抗マウスIgGまたはヤギ抗ウサギIgGと前記膜とを室温で1時間培養し、化学発光試薬Plus(Chemiluminescence Reagent Plus)で検出し、膜に暴露された。異なるMMP阻害剤で処理するか否かによる、タンパク質発現パターンを比較した。
<zLumicanプロモータートランスジェニック魚>
PCRプライマー:
順方向プライマーI:5’−ATAAGAATGCGGCCGCTCCATTAATTCGACAGACCAG−3’;
順方向プライマーII:5’−ATAAGAATGCGGCCGCAGGTAGACAACACGGTTATGT−3’;
逆方向プライマー:5’−CGACGCGTGGCTGCACAACTTAAATTAAACCT−3’;
<初期の薬物スクリーニングに用いられる化学物質>
Claims (1)
- 近視を治療する薬物を製造するための、MMP阻害剤の使用であって、
前記MMP阻害剤は、
MMP阻害剤としてテトラサイクリンを使用する場合、テトラサイクリンの濃度は、250μM〜2.5mMであり、
MMP阻害剤としてドキシサイクリンを使用する場合、ドキシサイクリンの濃度は、2μM〜2mMである、MMP阻害剤の使用。
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US20160067238A1 (en) | 2013-05-06 | 2016-03-10 | Philip Wu | Pharmaceutical composition and uses thereof |
US11021502B2 (en) * | 2014-08-04 | 2021-06-01 | The Trustees Of The University Of Pennsylvania | Transcriptome in vivo analysis (TIVA) and transcriptome in situ analysis (TISA) |
CN106053633A (zh) * | 2016-05-23 | 2016-10-26 | 上海欣峰制药有限公司 | 一种盐酸头孢吡肟的临床前药效评价方法 |
CN105950657A (zh) * | 2016-06-02 | 2016-09-21 | 贵州医科大学 | 转基因斑马鱼模型在筛选治疗g6pd缺乏症的药物中的应用 |
JPWO2019093262A1 (ja) * | 2017-11-07 | 2020-11-19 | 学校法人慶應義塾 | 腸内環境制御による近視抑制 |
KR102223999B1 (ko) * | 2019-08-12 | 2021-03-09 | 고려대학교 산학협력단 | 어류의 시력 등급화 방법 및 컴퓨터 판독 가능한 저장매체 |
KR102120159B1 (ko) * | 2018-10-31 | 2020-06-08 | 고려대학교산학협력단 | 어류의 시기능 평가 시스템 및 이를 이용한 안구 독성 약물 스크리닝 방법 |
WO2020091201A1 (ko) * | 2018-10-31 | 2020-05-07 | 고려대학교 산학협력단 | 어류의 시기능 평가 시스템 및 이를 이용한 안구 독성 약물 스크리닝 방법, 어류의 시력 등급화 방법 및 컴퓨터 판독 가능한 저장매체 |
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CN110463654B (zh) * | 2019-08-15 | 2021-09-07 | 贵州中医药大学 | 一种建立斑马鱼血管新生障碍模型的方法 |
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JPH04178359A (ja) * | 1990-07-01 | 1992-06-25 | Kuraray Co Ltd | テトラサイクリン誘導体 |
EP0692931A4 (en) * | 1993-04-07 | 1996-03-20 | Glycomed Inc | SYNTHETIC INHIBITORS OF MATRIX METALLOPROTEASE AND USES |
US6172057B1 (en) * | 1997-02-27 | 2001-01-09 | American Cyanamid Company | N-Hydroxy-2-(alkyl, aryl, or heteroaryl sulfanyl, sulfinyl or sulfonyl)-3-substituted alkyl, aryl or heteroarylamides as matrix metalloproteinase inhibitors |
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US6946453B2 (en) * | 1998-11-18 | 2005-09-20 | Collagenex Pharmaceuticals, Inc. | 4-dedimethylaminotracycline derivatives |
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