JP5256299B2 - 逆タンパク質 - Google Patents
逆タンパク質 Download PDFInfo
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- JP5256299B2 JP5256299B2 JP2010537208A JP2010537208A JP5256299B2 JP 5256299 B2 JP5256299 B2 JP 5256299B2 JP 2010537208 A JP2010537208 A JP 2010537208A JP 2010537208 A JP2010537208 A JP 2010537208A JP 5256299 B2 JP5256299 B2 JP 5256299B2
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- KERCOYANYUPLHJ-XGEHTFHBSA-N Thr-Pro-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O KERCOYANYUPLHJ-XGEHTFHBSA-N 0.000 description 1
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- MPKPIWFFDWVJGC-IRIUXVKKSA-N Tyr-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O MPKPIWFFDWVJGC-IRIUXVKKSA-N 0.000 description 1
- LHTGRUZSZOIAKM-SOUVJXGZSA-N Tyr-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N)C(=O)O LHTGRUZSZOIAKM-SOUVJXGZSA-N 0.000 description 1
- QHLIUFUEUDFAOT-MGHWNKPDSA-N Tyr-Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC1=CC=C(C=C1)O)N QHLIUFUEUDFAOT-MGHWNKPDSA-N 0.000 description 1
- OKDNSNWJEXAMSU-IRXDYDNUSA-N Tyr-Phe-Gly Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC(O)=O)C1=CC=C(O)C=C1 OKDNSNWJEXAMSU-IRXDYDNUSA-N 0.000 description 1
- IEWKKXZRJLTIOV-AVGNSLFASA-N Tyr-Ser-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O IEWKKXZRJLTIOV-AVGNSLFASA-N 0.000 description 1
- UEOOXDLMQZBPFR-ZKWXMUAHSA-N Val-Ala-Asn Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N UEOOXDLMQZBPFR-ZKWXMUAHSA-N 0.000 description 1
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- C07K2319/00—Fusion polypeptide
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Description
(NH2)Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu(COOH)
SEQ ID: NO: 1
(NH2)Ala-Ile-Lys-Ser-Pro-Cys-Gln-Arg-Glu-Thr-Pro-Glu-Gly-Ala-Glu-Ala-Lys-Gly-Gly-Cys-Pro-Ser-Thr-His-Val(COOH);
SEQ ID: NO: 2
(NH2)Lys-Ser-Pro-Cys-Gln-Arg-Glu-Thr-Pro-Glu-Gly-Ala-Glu-Ala-Lys-Gly-Gly-Cys-Pro-Ser(COOH);及び
SEQ ID:NO:3
(NH2)Cys-Gln-Arg-Glu-Thr-Pro-Glu-Gly-Ala-Glu-Ala-Lys-Gly-Gly-Cys(COOH)
を備える特に適したタンパク質が見出された。
急性肺損傷ALIの治療、
急性呼吸窮迫症候群ARDSの治療、
重症急性呼吸器症候群(SARS)の治療、
肺炎の治療、
多臓器不全の場合の治療、
呼吸により誘発される肺損傷、肺移植、輸液により誘発される肺損傷、治療目的のIL-2投与又は喘息の場合の治療、
が含まれ、例えば、上皮イオンチャネルの活性化、肺機能の改善及び/又は肺水腫等の水腫の治療である。
TFA塩 トリフルオロ酢酸塩
電気生理学的検査をヒトA549細胞(ATTC No. CCL-185)に行った。A549細胞は、ヒト肺上皮細胞であって、肺中の水及び電解質の拡散に関与する。該細胞を、1%のペニシリン−ストレプトマイシン及び10%のウシ胎仔血清を含むDMEM-F-12培地に懸濁させ、プラスチック製細胞培養容器に移し、空気95%及びCO2 5%で37℃のインキュベータで培養した。培地は週に2〜3回交換した。細胞は、約22時間以内に倍増し、7×104個/cm2を超える細胞密度にはならなかった。
「パッチ・クランプ」技術の「全細胞」及び「細胞接着」構造において、A549細胞から巨視的電流及び単一チャネル電流が放出された(Hamill et al, Pflugers Arch. 1981, 391 (2): 85-100, 1981)。「全細胞」構造における電流散逸に対して、以下に示す槽溶液及び電極溶液を用いた:
槽溶液:135 mMのメタンスルホン酸ナトリウム、10 mMのNaCl、2.7 mMのKCl、1.8 mMのCaCl2、2 mMのMgCl2、5.5 mMのグルコース及び10 mMのHEPES、pH 7.4。
電極溶液:120 mMのメチルスルホン酸カリウム、15mMのKCl、6 mMのNaCl、1mMのMg2ATP、2mMのNa3ATP、10 mMのHEPES及び0.5 mMのEGTA(pH 7.2)。
オスのウィスター系ラット(体重250g〜350g)をRompun(登録商標)(0.02ml/100g)及びKetavet(登録商標)(0.1ml/100g)で麻酔する。呼吸は、72blows/分のサイクルで行われ、吸入時間が0.2秒で、呼気時間が0.5秒である。体温は、平均で37℃〜39℃の範囲である。正常状態で、PaO2(動脈の酸素分圧)は、500〜550mmHgの範囲である。急性肺損傷のシミュレーション及び肺水腫の形成のため、肺を酸性食塩水(pH 5)で7〜9回すすぎ洗いする。1時間後、アミノ酸配列SEQ ID NO: 1、SEQ ID NO: 2又はSEQ ID NO: 3を備えるタンパク質を滅菌食塩水に溶解させ、いずれの場合も、霧状で気管内に投与する(最大投与量:0.5ml)。それぞれ60分間隔で、動物から動脈血(0.1ml)を抜き、酸素含有量を通常値に対する%で決定する。アミノ酸配列SEQ ID NO: 1、SEQ ID NO: 2又はSEQ ID NO: 3を備えるタンパク質を投与した後、図3A、図3B又は図3Cから明らかなように、血液中の酸素含有量は増加する。また、例7も参照されたい。
本発明に従うタンパク質、例えばアミノ酸配列SEQ ID NO: 1、SEQ ID NO: 2又はSEQ ID NO: 3を備えるタンパク質の肺機能への刺激的効果の検証を、肺水腫を誘発させた実験動物研究によって行う。実験手順は、例6に記載される。測定値を客観的にするため、いずれの場合も、5匹の動物を使用する。
気管内吸入については、それぞれの場合で125μgのタンパク質をpH 7.3の150mMの食塩水に溶解させる。動脈血の酸素含有量は、肺のすすぎ洗いを行う直前、肺のすすぎ洗いの60分後、肺のすすぎ洗いの180分後に測定される。肺のすすぎ洗いを行う直前の酸素含有量が100%であると決定する。それぞれの最終的な肺のすすぎ洗いの60分後、血中の酸素含有量は、平均でほんの20%になる。酸素含有量のパーセンテージは、3時間以内に、アミノ酸配列SEQ ID NO: 1を備えるタンパク質で治療を行う場合で60%の値まで上昇し、アミノ酸配列SEQ ID NO: 2を備えるタンパク質で治療を行う場合で63%の値まで上昇し、アミノ酸配列SEQ ID NO: 3を備えるタンパク質で治療を行う場合で70%の値まで上昇する。
タンパク質を加えないと、肺機能の改善(酸素含有量20%)は、肺のすすぎ洗いから180分以内で起きないであろう。
上記結果は、
SEQ ID NO: 1のアミノ酸配列を備えるタンパク質に関しては図3Aで説明され、
SEQ ID NO: 2のアミノ酸配列を備えるタンパク質に関しては図3Bで説明され、
SEQ ID NO: 3のアミノ酸配列を備えるタンパク質に関しては図3Cで説明される。
ヒトの新鮮血は、炎症促進性分子に対して極めて鋭敏な反応を示し、とりわけ、炎症マーカーのインターロイキン−6(IL-6)を放出する場合である。炎症促進反応を測定するため、異なる濃度のアミノ酸配列SEQ ID NO: 3を備えるタンパク質を有するヒト新鮮血のサンプルを、10μg/ml、3μg/ml、1μg/mlの濃度でインキュベートした。37℃で24時間インキュベートした後、ELISAによって溶液中の炎症マーカーインターロイキン-6を定量的に測定した。LPSは、ポジティブコントロールとして機能を果たした。
このようにして、表2に示す測定データが得られ、該測定データは、LPSと比較してSEQ ID NO: 3のアミノ酸配列を備えるタンパク質が及ぼす影響を示す。
Claims (5)
- アミノ酸配列
SEQ ID: NO: 1
(NH2)Ala-Ile-Lys-Ser-Pro-Cys-Gln-Arg-Glu-Thr-Pro-Glu-Gly-Ala-Glu-Ala-Lys-Gly-Gly-Cys-Pro-Ser-Thr-His-Val(COOH);
SEQ ID:NO: 2
(NH2)Lys-Ser-Pro-Cys-Gln-Arg-Glu-Thr-Pro-Glu-Gly-Ala-Glu-Ala-Lys-Gly-Gly-Cys-Pro-Ser(COOH);及び
SEQ ID:NO: 3
(NH2)Cys-Gln-Arg-Glu-Thr-Pro-Glu-Gly-Ala-Glu-Ala-Lys-Gly-Gly-Cys(COOH)
から選択されるタンパク質であって、
各タンパク質において、2つのシステイン部分間の結合により閉環が存在することを特徴とするタンパク質。 - 塩の形態である請求項1に記載のタンパク質。
- 請求項1又は2に記載のタンパク質を備えることを特徴とする薬剤。
- 薬剤として使用するための請求項1又は2に記載のタンパク質。
- 肺機能の改善及び/又は水腫の治療用の薬剤を調製するための請求項1又は2に記載のタンパク質の使用。
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ATA2015/2007 | 2007-12-12 | ||
AT0201507A AT506151B1 (de) | 2007-12-12 | 2007-12-12 | Fusionsprotein |
PCT/AT2008/000447 WO2009073908A1 (de) | 2007-12-12 | 2008-12-12 | Reverses protein |
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US4894439A (en) * | 1986-05-22 | 1990-01-16 | Cetus Corporation | N-terminal derivatives of tumor necrosis factor purified by microporous PTFE membranes |
DE3841759A1 (de) | 1988-12-12 | 1990-06-13 | Basf Ag | Neue tnf-peptide |
EP1105152A1 (en) | 1998-08-14 | 2001-06-13 | Innogenetics N.V. | Tnf-derived peptides for use in treating oedema |
EP1452868A2 (en) * | 2003-02-27 | 2004-09-01 | Pepscan Systems B.V. | Method for selecting a candidate drug compound |
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2007
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HK1146905A1 (en) | 2011-07-22 |
DK2219663T3 (da) | 2013-01-07 |
AT506151A1 (de) | 2009-06-15 |
EP2219663B1 (de) | 2012-11-28 |
US20110021411A1 (en) | 2011-01-27 |
CA2707850A1 (en) | 2009-06-18 |
EP2219663A1 (de) | 2010-08-25 |
ES2400316T3 (es) | 2013-04-09 |
AT506151B1 (de) | 2010-01-15 |
JP2011506346A (ja) | 2011-03-03 |
US8372799B2 (en) | 2013-02-12 |
WO2009073908A1 (de) | 2009-06-18 |
EP2219663B9 (de) | 2013-01-23 |
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