JP7427084B2 - 「血管内血栓」溶解剤 - Google Patents
「血管内血栓」溶解剤 Download PDFInfo
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- JP7427084B2 JP7427084B2 JP2022521957A JP2022521957A JP7427084B2 JP 7427084 B2 JP7427084 B2 JP 7427084B2 JP 2022521957 A JP2022521957 A JP 2022521957A JP 2022521957 A JP2022521957 A JP 2022521957A JP 7427084 B2 JP7427084 B2 JP 7427084B2
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- thrombus
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- acid sequence
- thrombolytic
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/482—Serine endopeptidases (3.4.21)
- A61K38/484—Plasmin (3.4.21.7)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
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Description
「血管内血栓」を認識して血栓を溶解させるポリペプチドであるHtrA1とHtrA2は、組換えタンパク質で準備した。このために、血管内血栓ドメインと血栓溶解ドメインの両方を含むHtrA1アミノ酸配列(配列番号9)の157~480に該当するcDNAをフォワードプライマー(5’-AATTCATATGCAAGGGCAGGAAGATCCCA-3’)(配列番号11)とリバースプライマー(5’-TATCTCGAGCTATGGGTCAATTTCTTCGGG-3’)(配列番号12)を用いてPCRによって増幅させた。PCR条件は、initial denaturation 95℃で5分後、増幅(95℃で30秒、63℃で1分、72℃で2分)過程を34回繰り返し行った後、72℃で10分行った。これを発現ベクターであるpET28a+発現ベクター(expression vector)(Novagen社製、USA)のNdeI/XhoI部位にサブクローニングした。得られたHtrA1組換えプラスミドをE.coli BL21(DE3)pLysS(Stratagene社製、USA)にエレクトロポレーション(electroporation)させた後、培養しながらIPTGを添加してHtrA1を発現させた。組換えE.coli培養液を超音波処理して細胞溶解液(cell lysate)を作製し、これをエコノパッククロマトグラフィーカラム(econo-pac chromatography column)(Bio-Rad社製)に通して分離した後、PD-10カラム(Amersham社製、US)で精製することにより、組換えタンパク質HtrA1を得た。HtrA2の場合、HtrA2アミノ酸配列(配列番号10)の134~458に該当するcDNAを、フォワードプライマー(5’-GTCCTCGCCCATATGGCCGTCCCTAGCC-3’)(配列番号13)とリバースプライマー(5’-GGCTCTCGAGTCATTCTGTGACCTCAGGG-3’)(配列番号14)を用いてPCRによって増幅させた。PCR条件は、initial denaturation 95℃で5分後、増幅(95℃で30秒、65℃で45秒、72℃で1分)過程を34回繰り返し行った後、72℃で10分行った。これを得た後、HtrA1などの方法でpET28a+発現ベクター(Novagen社製、USA)にサブクローニングし、しかる後に、発現させることにより、組換えタンパク質HtrA2を得た。
現在の血栓溶解剤医薬品の血栓溶解機序は、プラスミノゲン(plasminogen)をプラスミン(plasmin)に活性化させ、プラスミン依存性血栓溶解(plasmin-dependent fibrinolysis)が起こる作用機序である。既存の血栓溶解酵素と比較して作用機序を確認するために、まず、プラスミノゲン(1.23μM)とプラスミン特異的蛍光基質Boc-Glu-Lys-Lys-MCA(100μM)に各血栓溶解酵素(0.1mg/ml)を添加した後、培養した。プラスミンに対するプラスミノゲンの活性化は、プラスミンによって溶解した基質の蛍光強度を測定することにより確認した。実際のプラスミノゲンの活性化により生成されるプラスミンバンドは、各酵素(0.15mg/ml)をプラスミノゲン(5.14μM)で処理した後、SDS-PAGEによって確認した。
HtrA1の血栓特異性を評価するために、創傷治癒過程で現れるフィブリノリシス成分(fibrinolysis components)に対する活性の有無を確認した。このために、フィブリノゲン(fibrinogen)をトロンビン(trombin)と反応させて得られたフィブリンクロット(fibrin clot)を50mM Tris-HCl対照群又は血栓溶解酵素(2mg/ml)と37℃で24時間培養した。フィブリンクロットの溶解は、分光光度計を用いて415nmの波長で測定した。フィブリノゲンに対するHtrA1の活性を確認するために、フィブリノゲン(5μM)を50mM Tris-HCl対照群又は各血栓溶解酵素(0.15mg/ml)と37℃で3時間培養した後、フィブリノゲンの分解の有無をSDS-PAGEによって確認した。フィブロネクチンに対するHtrA1の活性を確認するために、フィブロネクチン(fibronectin)(1.52μM)を各血栓溶解酵素(0.15mg/ml)と共に37℃で3時間培養した後、4~12%SDSゲル上で分離してanti-cFN又はanti-pFN抗体で免疫染色した。
本発明の成果物による血栓症治療効能を評価するために、尾血栓症モデルを用いた動物実験を行った。κ-カラギーナン(κ-carrageenan)誘導尾血栓症モデルは、15週齢の雌BALB/cマウスで確立された。尾血栓症を有するマウスの各群(n=8)に生理食塩水(対照群)又は各血栓溶解酵素を腹腔内に注射し、24時間後に血栓症部位の長さ及び割合を測定し、その結果を表3及び表4に示した。
次に、血栓塞栓症の予防及び治療効能を評価するために、肺血栓塞栓症モデルを用いた動物実験を行った。アデノシン5’-ジホスフェート(ADP、Adenosine 5’-diphosphate)によって誘導された肺血栓塞栓症モデルは、15週齢の雌C57BL/6マウスで確立された。肺血栓塞栓症マウスの各群(n=8)を12時間以上絶食させた後、生理食塩水(対照群)又は血栓溶解酵素を40mg/kgの用量で静脈内注射した。30分後、マウスにADP(150mg/kg)を注射して肺血栓塞栓症を誘導した後、死亡したか否かを確認し、その結果を表5及び表6に示した。
血栓溶解タンパク質HtrA1の投与時に、創傷治癒過程で体内出血の危険性を確認するために、15週齢のC57BL/6雌マウスを用いて尾出血検査を行った。生理食塩水(対照群)又は各血栓溶解酵素を40mg/kgの用量でマウス群(n=5)に静脈注射した。30分間後、麻酔したマウスから尾を切断し、出血が止まるまで血液を集めながら出血時間及び出血量を記録した。集められた血液に対しては、ヘモグロビン含有量を測定した。また、マウスの切断された尾静脈での血液凝固に必要な時間を記録した。
Claims (4)
- (a)配列番号1に示されるアミノ酸配列及び配列番号3に示されるアミノ酸配列からなるか、或いは、
(b)配列番号2に示されるアミノ酸配列及び配列番号4に示されるアミノ酸配列からなる、
ことを特徴とする、血管内血栓を認識して血栓を溶解させるポリペプチド。 - (a)配列番号1に示されるアミノ酸配列と90%以上の同一性を有するアミノ酸配列及び配列番号3に示されるアミノ酸配列と90%以上の同一性を有するアミノ酸配列からなるか、或いは、
(b)配列番号2に示されるアミノ酸配列と90%以上の同一性を有するアミノ酸配列及び配列番号4に示されるアミノ酸配列と90%以上の同一性を有するアミノ酸配列からなる、
ことを特徴とする、血管内血栓を認識して血栓を溶解させるポリペプチド。 - (a)配列番号1に示されるアミノ酸配列及び配列番号3に示されるアミノ酸配列を含むか、或いは、
(b)配列番号2に示されるアミノ酸配列及び配列番号4に示されるアミノ酸配列を含む、
ことを特徴とする、血管内血栓を認識して血栓を溶解させるポリペプチドを有効成分として含むことを特徴とする、血栓症治療又は予防用薬学的組成物。 - (a)配列番号1に示されるアミノ酸配列と90%以上の同一性を有するアミノ酸配列及び配列番号3に示されるアミノ酸配列と90%以上の同一性を有するアミノ酸配列を含むか、或いは、
(b)配列番号2に示されるアミノ酸配列と90%以上の同一性を有するアミノ酸配列及び配列番号4に示されるアミノ酸配列と90%以上の同一性を有するアミノ酸配列を含む、
ことを特徴とする、血管内血栓を認識して血栓を溶解させるポリペプチドを有効成分として含むことを特徴とする、血栓症治療又は予防用薬学的組成物。
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JP2003517269A (ja) | 1998-04-28 | 2003-05-27 | アクシス・ファーマシューティカルズ・インコーポレイテッド | インスリン様生長因子結合タンパク質を選択的に開裂し得る新規セリンプロテアーゼ |
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