JP2020502056A - 糖尿病、高血圧および高コレステロール血症を治療するための組成物および方法 - Google Patents
糖尿病、高血圧および高コレステロール血症を治療するための組成物および方法 Download PDFInfo
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Abstract
Description
本明細書では、本発明の異なる態様を説明するために以下の用語が使用されている。これらの用語は説明の目的でのみ使用されており、本発明の任意の態様の範囲を限定することを意図していない。
驚くべきことに、切断型フラグメントを含む精製された単離40sリボソームタンパク質S2(RPS2)は、被験体に投与された場合に、血糖値を低下させ、血糖値を正常化し、血中コレステロール値を低下させ、血圧レベルを低下させかつ正常化し、ヘモグロビンA1cレベルを低下させ、グルカゴンレベルを低下させ、インスリン抵抗性を減少させる能力を含む治療上の利点を示すことが発見された。参考として、40s RPS2は、リボソームタンパク質のS5Pファミリーに属するタンパク質である。ヒトに関しては、RPS2遺伝子は、40Sサブユニットの構成要素であり、かつ細胞質に位置するリボソームタンパク質をコードする。
MADDAGAAGGPGGPGGPGMGNRGGFRGGFGSGIRGRGRGRGRGRGRGRGARGGKAEDKEWMPVTKLGRLVKDMKIKSLEEIYLFSLPIKESEIIDFFLGASLKDEVLKIMPVQKQTRAGQRTRFKAFVAIGDYNGHVGLGVKCSKEVATAIRGAIILAKLSIVPVRRGYWGNKIGKPHTVPCKVTGRCGSVLVRLIPAPRGTGIVSAPVPKKLLMMAGIDDCYTSARGCTATLGNFAKATFDAISKTYSYLTPDLWKETVFTKSPYQEFTDHLVKTHTRVSVQRTQAPAVATT
GHVGLGVKCSKEVATAIRGAIILAKLIVPVRRGYWGNKIGKPHTVPCKVTGRCGSVLVRLIPAPRGTGIVSAPVPKKLLMMAGIDDCYTSARGCTATLGNFAKATFDAISKTYSYLTPDLWKETVFTKSPYQEFTDHLVKTHTRVSVQRTQAPAVATT
SIVPVRRGYWGNKIGKPHTVPCKVTGRCGSVLVRLIPAPRGTGIVSAPVPKKLLMMAGIDDCYTSARGCTATLGN
GHVGLGVKCSKEVATAIRGAIILAKLSIVPVRRGYWGNKIGKPHTVPCKVTGRCGSVLVRLIPAPRGTGIVSAPVPKKLLMMAGIDD
MADDAGAAGGPGGPGGPGMGNRGGFRGGFGSGIRGRGRGRGRGRGRGRGARGGKAEDKEWMPVTKLGRLVKDMKIKSLEEIYLFSLPIKESEIIDFFLGASLKDEVLKIMPVQK QTRAGQRTRFKAFVAIGDYN
ヒト40Sリボソームタンパク質S2をコードするRPS2遺伝子、および種々のペプチド部分をpMAL−5ベクター(New England Biolabs)にサブクローニングした。フォワードプライマー(配列:atggcggatgacgccggtgc)およびリバースプライマー(配列:ctatgttgtagccacagctgg)を用いてRPS2遺伝子を増幅し、得られたPCR断片をリン酸化し、低融点アガロースから精製した。得られた配列をpMAL−5ベクターにライゲーションし、ライゲーションおよびインキュベーションの後、100μg/mlのアンピシリンを含有するLBプレート上に広げ、37℃で一晩インキュベートしてインビボタンパク質産生用の形質転換体を作製した。
RPS2形質転換体を5mlのブロスに接種し、2×108細胞/mlまで増殖させた。この培養物を使用して、200mLのLB amp 0.2%グルコースを約0.5のA600に接種した。次いで、この培養物を、ITPG(イソプロピルチオ−β−ガラクトシド)を終濃度が0.3mMになるように添加することによって誘導し、30℃でさらに4時間増殖させた。次に細胞を遠心分離し、培養液1リットル当たり25mlのカラム緩衝液に再懸濁した。この細胞を凍結融解によって溶解し、続いて20ゲージの針を通して継代した。溶解した細胞を遠心分離し、25mlのクルード抽出物ごとに125mlの冷CBを添加することによって上清を希釈した。希釈したクルード抽出物を15mlのアミロースカラムに加え、12カラム容量のCBで洗浄した。タンパク質をCBおよびマルトース(10mM)で溶出した。得られた溶出液を、200μg/mlに希釈した1μlの第Xa因子と共に室温で4時間インキュベートした。融合タンパク質切断混合物をpH8.0で透析し、アミラーゼカラムを緩衝液で洗浄し、融合タンパク質切断混合物をカラムにロードした。フロースルーを回収し、単離タンパク質の量をビシンコニン酸アッセイ(BSA)アッセイによって決定し、タンパク質の量をELISAによって評価した。
ラットのズッカー糖尿病脂肪(ZDF)株は広く知られており、肥満、ならびに高血圧および高コレステロールに関連する2型糖尿病を研究するために一般的に使用されている。ZDF株は早発性糖尿病の近交系ラットモデルであり、すべてのfa/fa雄ラットが、Purina5008(Charles River Laboratories International, Inc., MA, USA)の特別食を与えられると、10〜12週齢で糖尿病を発症する。表現型は同質であり、主にその株が遺伝的に近交系であるという事実と特別な食事療法が提供されるという事実とに起因する。
IMG−1が2型糖尿病動物モデルにおいて血糖値を正常化し、HA1Cを減少させることが示されたので、IMG−1が1型糖尿病動物モデルにおいて血糖値に影響を及ぼし得るかどうかを確かめた。糖尿病はストレプトゾトシン(STZ)を使用することによってマウスで誘発することができ、STZは膵臓β細胞に対する選択的な毒性を有し、げっ歯類における実験的糖尿病の誘発のために広く使用されている化学物質である化合物である。STZは、ストレプトマイセスアクロモジェンス細菌によって産生される抗生物質であり、膵臓β細胞に細胞毒性作用を及ぼす高反応性メチルニトロソ尿素部分に結合するグルコース分子(デオキシ形態)を含む。
スプラーグドーリーモデルを用いて、IMG−1製剤のクリアランスおよび毒性にアクセスした。3匹のオスのスプラーグドーリーラットに静脈内投与によって20μgの活性化合物(配列番号1に対応)を処理し、続いて間隔を置いて採血した。具体的には、0、IMG−1投与後5分、15分、30分、60分、90分、2時間、4時間、6時間、24時間、および48時間である。図9に示すように、6時間にわたって測定したIMG−1活性化合物の血清レベル(pg/mL)によって、活性化合物は、投与後2時間までに3匹すべての動物の血液中で検出され、3匹目の動物では処置後4時間まで検出可能なレベルを示した。活性化合物のレベルと共に、血糖値をスプラーグドーリーモデルで評価した。IMG−1投与はZDFラットの血糖値を劇的に低下させたが、スプラーグドーリーラットに投与された単回投与のIMG−1製剤(20μg)は、スプラーグドーリー動物における48時間にわたる血糖値によってみられるように、48時間以内に低血糖を促進することはなかった(図9を参照)。
インスリン分泌および抵抗性を定量化するための最も広く受け入れられている試験方法は、正常血糖インスリンクランプ法であり、これは動物がどの程度グルコースを代謝するか、または動物がインスリンに対してどのくらい敏感であるかを測定する。この手順では、絶食時より高い一定の血漿インスリンレベルを維持するように外因性インスリンを注入しながら、グルコースを様々な速度で注入することによってグルコースを基礎レベル(100〜150mg/dl)に固定する。
全長精製RPS2タンパク質を、2つの位置(P1位のAsn及びP1位のGlyのアミノ酸134)でRPS2を切断し、2つのサブユニットを得るヒドロキシルアミン(NH2OH)で消化し、約13kDaのRPS2−short(IMG−1S)および約18kDaのRPS2−long(IMG−1L)と命名した。得られたフラグメントを非変性ポリアクリルアミドゲルで分離し、可視化した後、ゲルから電気溶出した。このフラグメントを使用して細胞培養で試験するための製剤を調製した。
本発明は、配列ID番号1、配列ID番号2、配列ID番号3、および/または配列ID番号4のうちの1つまたは以上に対応する1つまたは以上のポリペプチド、ペプチド、および/または類似体を有する医薬組成物を提供する。
Claims (21)
- 40sリボソームタンパク質S2(RPS2)もしくはそのフラグメントを有し、またはそれからなる単離ポリペプチドであって、配列ID番号1、2、3、または4のアミノ酸配列と少なくとも50%の配列同一性を有するアミノ酸配列を有する、ポリペプチド。
- 請求項1に記載のポリペプチドにおいて、前記RPS2またはそのフラグメントが、配列ID番号1、2、3、または4のアミノ酸配列と少なくとも55%、60%、65%、70%、75%、80%、85%、90%、95%、98%、または99%の配列同一性を有する、ポリペプチド。
- 請求項1または2に記載のポリペプチドにおいて、前記RPS2またはそのフラグメントが、配列ID番号1、2、3、または4のアミノ酸配列を有する、ポリペプチド。
- 上述の請求項のいずれかに記載のポリペプチドにおいて、前記RPS2またはそのフラグメントが、配列ID番号1、2、3、または4のアミノ酸配列からなる、ポリペプチド。
- 上述の請求項のいずれかに記載の少なくとも1つのポリペプチドを有する製剤。
- 前記製剤が経口医薬製剤である、請求項5に記載の製剤。
- 前記製剤が非経口医薬製剤である、請求項5に記載の製剤。
- 請求項5〜7のいずれかに記載のポリペプチドにおいて、前記製剤が、1またはそれ以上の医薬的に許容される担体、および/または1またはそれ以上の医薬的に許容される希釈剤、および/または1またはそれ以上の医薬的に許容される賦形剤を有する、製剤。
- 前記製剤が水性医薬製剤である、請求項5〜8のいずれかに記載の製剤。
- 前記ペプチドが0.05〜5μg/Lの濃度で存在する、請求項9に記載の製剤。
- 前記ペプチドが、0.1〜1μg/Lの濃度で存在する、請求項9に記載の製剤。
- 前記水性医薬製剤が緩衝剤、選択的に生理学的pHを有する緩衝剤を有する、請求項9〜11のいずれかに記載の製剤。
- 前記緩衝剤がリン酸緩衝生理食塩水である、請求項12に記載の製剤。
- 請求項1〜4のいずれかに記載のポリペプチドまたは請求項5〜13のいずれかに記載の製剤を有する薬剤。
- 疾患を治療する方法に使用するための、請求項1〜4のいずれかに記載のポリペプチドまたは請求項5〜13のいずれかに記載の製剤。
- 1型および/または2型糖尿病を治療する方法に使用するための、請求項1〜4のいずれかに記載のポリペプチドまたは請求項5〜13のいずれかに記載の製剤。
- 請求項16に記載のポリペプチドまたは製剤において、前記使用が、肝グルコース産生の減少、および/またはコレステロールレベルの減少、および/またはグルカゴンレベルの減少、および/またはインスリン抵抗性の減少、および/または血圧の低下を提供する、ポリペプチドまたは製剤。
- 高血糖症、および/または高コレステロール血症、および/または高血圧症、および/またはメタボリックシンドロームのうちの少なくとも1つの治療に使用するための、請求項1〜4のいずれかに記載のポリペプチドまたは請求項5〜13のいずれかに記載の製剤。
- 1型および/または2型糖尿病を治療するための薬剤を製造するための、請求項1〜4のいずれかに記載の少なくとも1つのポリペプチドの使用。
- 高血糖症、および/または高コレステロール血症、および/または高血圧症、および/またはメタボリックシンドロームのうちの少なくとも1つを治療するための薬剤を製造するための、請求項1〜4のいずれかに記載の少なくとも1つのポリペプチドの使用。
- 対象における糖尿病、および/または高血糖症、および/または高コレステロール血症、および/または高血圧症のうちの少なくとも1つを治療する方法であって、請求項5〜13のいずれかに記載の製剤を前記対象に投与する工程を有する、方法。
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