JP2021130704A - At2r活性を調節するための組成物および方法 - Google Patents
At2r活性を調節するための組成物および方法 Download PDFInfo
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Abstract
Description
いてNuytらによって報告されているように、AT2R mRNAは、視床下部外側野の分化初期に(例えば、胎生13日目という初期に)出現したが、さまざまな発育中/分化中の脳構造に出現したのは一時的であった(38)。ほとんどの領域において、AT2R mRNA発現の個体発生は、さまざまな領域自体(成熟ニューロンにおいてAT2R発現が劇的に減少する、小脳、下オリーブ複合体、ならびに舌、口周囲、および顎の筋肉の神経を支配する延髄運動核のような)の成熟および分化と高度に相関している。
[0014]心血管疾患(CVD)の発生に寄与する炎症カスケードは、罹患率の著しい上昇がきっかけとなって、ここ10年の間に急速に解明されてきている。これを秩序だって説明すると、すべての1型真性糖尿病(T1DM)致死率のほぼ70%は該病態に起因する(51)。炎症性AT1Rの活性化増大は、心血管疾患および高血圧に見られる(3)。一般に、AT1Rの活性化増大は、NF−κB、IL−6などの炎症性およびがん誘発性(pro-cancerous)タンパク質を上方制御する(52、53、54)。
は、ミトコンドリアの内膜に位置するAT2Rは、ミトコンドリア呼吸の介在に重要な役割を果たす。老化の過程で、ミトコンドリアのAT2R発現は減少する一方、炎症性AT1Rの発現は増大することが知られている(62)。老化におけるMASの重大な役割は、この系がアルツハイマー病(AD)の発症において役割を果たすことを示している。さらなる裏付けでは、アミロイドβは、AT2R受容体のオリゴマー化増加および機能喪失をもたらすことが示されており、これが疾患の発生機序に寄与すると考えられている(63、64)。
個のアミノ酸残基を含むポリペプチド(またはポリペプチド誘導体もしくは類似体)である。したがって、本発明のAT2Rアゴニストとしては、以下の配列のいずれかを含むか、いずれかから成るか、本質的にいずれかから成るポリペプチド(またはポリペプチド誘導体もしくは類似体)が挙げられる:Lys−Pro−Leu−Lys−Pro−Trp;Lys−3Hyp−Leu−Lys−Pro−Trp;Lys−4Hyp−Leu−Lys−Pro−Trp;Lys−Pro−Ile−Lys−Pro−Trp;Lys−3Hyp−Ile−Lys−Pro−Trp;Lys−4Hyp−Ile−Lys−Pro−Trp;Lys−Pro−Leu−Lys−3Hyp−Trp;Lys−3Hyp−Leu−Lys−3Hyp−Trp;Lys−4Hyp−Leu−Lys−3Hyp−Trp;Lys−Pro−Ile−Lys−3Hyp−Trp;Lys−3Hyp−Ile−Lys−3Hyp−Trp;Lys−4Hyp−Ile−Lys−3Hyp−Trp;Lys−Pro−Leu−Lys−4Hyp−Trp;Lys−3Hyp−Leu−Lys−4Hyp−Trp;Lys−4Hyp−Leu−Lys−4Hyp−Trp;Lys−Pro−Ile−Lys−4Hyp−Trp;Lys−3Hyp−Ile−Lys−4Hyp−Trp;およびLys−4Hyp−Ile−Lys−4Hyp−Trp。いくつかの態様では、A2がProである場合、A5は3Hypまたは4Hypである。いくつかの態様では、A5がProである場合、A2は3Hypまたは4Hypである。
細胞死、メタボリックシンドローム)、(j)炎症が介在する腎障害、(k)炎症が介在する肝疾患(例えば、肝がん、肝機能不全)、(l)炎症が介在する心血管疾患(例えば、心筋の虚血および損傷、心筋線維症、心臓発作)、(m)膵炎、(n)筋肉量不足(例えば、疾病またはがんの処置に起因する筋肉消耗)、(o)AT1Rが介在するNHE6分解、(p)不十分なミトコンドリア活性、ならびに(q)不十分なMTOR、NHE6、ErbB3、一酸化窒素合成酵素、MCL−1、またはプロスタグランジン12−IPの活性または産生を特徴とする疾患、病態、または障害が挙げられる。
参考文献および定義
[0032]本明細書中で参照する特許および科学文献は、当業者が利用可能な知識を確立している。本明細書中で引用する発行済み米国特許、係属中の米国出願、公開された外国特許および出願、ならびに、タンパク質およびヌクレオチドのデータベース配列を含む参考文献は、各々が具体的かつ個別に援用されると示されているのと同程度に、本明細書に援用される。
[0034]本明細書中で用いる場合、「1つの(a)」という用語は1以上を意味する。
いことを意味する。
[0037]本明細書中で用いる場合、「医薬的に許容される」という語は、生理学的に容認することができ、哺乳動物に投与したときに典型的には重篤なアレルギー反応、発熱反応、または同様の望ましくない反応を引き起こさない、分子の実体および組成を表す。
AT2R活性のポリペプチドモジュレーター
[0039]本発明は、一般的配列A1−A2−A3−A4−A5−A6を有する6個のアミノ酸残基を含むポリペプチド(またはポリペプチド誘導体もしくは類似体)である新規クラスのアゴニストを提供するものであり、式中、A1はLysであり;A2はPro、3Hyp、または4Hypであり;A3はLeuまたはIleであり;A4はLysであり、A5はPro、3Hyp、または4Hypであり、A6はTrpである。この新規クラスをNP−6AKアゴニストと称する。少なくとも1つの位置にHypがある配列は、安定性が増大するため好ましい可能性がある。医薬用試薬として用いるためのこれらアゴニストの他の誘導体または類似体は、血流中での安定性を増大させる化学修飾を包含し得る。
グルコサミン、D−ガラクトサミン、D−グルコース、およびノイラミン酸を含む分枝または非分枝多糖、例えば、ラクトース、アミロペクチン、デンプン、ヒドロキシエチルデンプン、アミロース、硫酸デキストラン、デキストラン、デキストリン、グリコーゲン、あるいは糖アルコールのポリマー、例えば、ポリソルビトールおよびポリマンニトール、ヘパリンまたはヘパランなどの天然ポリマーも有用である。ポリマーの分子量は、約10000〜500000ダルトン(D)の範囲にあることができ、典型的には、約20000D、約30000D、約40000D、または約50000Dであることができる。
AT2Rアゴニスト試薬
[0046]上記したAT2Rの多くの作用に起因して、実験室試験におけるAT2Rの活性化は非常に興味深い。したがって、1つの観点では、本発明は、実験室での研究のためのin vitroまたはin vivo試薬としてのAT2Rアゴニストを提供する。
処置方法
[0050]AT1Rが介在する炎症性応答、またはAT2Rの活性化不足に起因する炎症性応答、および/またはそれらに起因する症状を処置するために、NP−6AKアゴニストを、病変細胞への活性作用物質の送達を可能にする任意の経路により投与する。いくつかの態様では、投与は皮下、筋肉内、腹腔内投与であるが、吸入、動脈内、静脈内、皮内、局所、経口、非経口、心室内、または頭蓋内投与によることもできる。あるいは、活性作用物質は、任意の適した手段により全身にまたは病変細胞に局所的に送達することができる。
医薬配合物
[0052]局所投与または化粧用途に適したローションなどの液体形態は、適した水性または非水性ビヒクルを、緩衝剤、懸濁化剤および分配剤、増粘剤、浸透促進剤などと一緒に包含することができる。クリームまたはペーストなどのような固体形態は、例えば、基材
として以下の成分のいずれか、水、油、アルコール、またはグリースを、界面活性剤、ポリエチレングリコールなどのポリマー、増粘剤、固形分などと一緒に包含することができる。液体または固体配合物は、リポソーム、ミクロソーム、マイクロスポンジなどのような向上した送達技術を包含することができる。
[0057]経口投与用組成物は、バルクの液体溶液もしくは懸濁液、またはバルクの粉末の形態をとることができる。しかしながら、より一般的には、該組成物は、正確な投薬を促進するために、単位剤形の形で存在する。「単位剤形」という用語は、ヒト被験者および他の哺乳動物のための単位投与量として適した物理的に別個の単位を表し、各単位は、適した医薬用溶媒と共同して望ましい治療効果をもたらすように計算して予め決定された分量の活性材料を含有する。典型的な単位剤形としては、液体組成物のプロファイルされ予め測定されているアンプルもしくはシリンジ、または、固体組成物の場合は、丸剤、錠剤、カプセルなどが挙げられる。1つの態様によれば、本発明のアゴニスト組成物は、通常は微量成分であり(約0.01〜約20重量%、または好ましくは約0.1〜約1.5重量%)、残余は、さまざまなビヒクルまたはキャリヤーと、所望の剤形を形成するのに有用な加工助剤である。
本願は以下の発明を包含する。
[項目1] AT2Rタンパク質を発現する細胞において、AT2Rタンパク質を活性化する方法であって、
式:A1−A2−A3−A4−A5−A6、
式中:
A1は、Lysであり
A2は、Pro、3Hyp、または4Hypであり
A3は、LeuまたはIleであり
A4は、Lysであり
A5は、Pro、3Hyp、または4Hypであり、そして
A6は、Trpである、
に相当するアミノ酸配列を含むAT2Rアゴニストの有効量を該細胞に提供することを含む、前記方法。
[項目2] AT2Rタンパク質を発現する細胞において、AT1Rタンパク質を阻害する方法であって、
式:A1−A2−A3−A4−A5−A6、
式中:
A1は、Lysであり
A2は、Pro、3Hyp、または4Hypであり
A3は、LeuまたはIleであり
A4は、Lysであり
A5は、Pro、3Hyp、または4Hypであり、そして
A6は、Trpである、
に相当するアミノ酸配列を含むAT2Rアゴニストの有効量を該細胞に提供することを含む、前記方法。
[項目3] AT2Rの活性化不足、またはMTOR、NHE6、ErbB3、一酸化窒素合成酵素、MCL−1、およびプロスタグランジン12−IPから成る群より選択されるAT2Rの下流エフェクターの不十分な活性もしくは産生、を特徴とする病態の処置を必要とする哺乳動物にアゴニストを投与する、項目1に記載の方法。
[項目4] 病態が、糖尿病、ErbB3の機能不全に関与するがん、および高血圧から成る群より選択される、項目3に記載の方法。
[項目5] AT2Rアゴニストを、自閉症、ALS、アルツハイマー病、パーキンソン病、筋ジストロフィー、およびハンチントン病から成る群より選択される神経学的病態の処置を必要とする哺乳動物に投与する、項目1に記載の方法。
[項目6] AT2Rアゴニストを、脊髄損傷、外傷性脳損傷、および脳病変から成る群より選択される損傷の処置を必要とする哺乳動物に投与する、項目1に記載の方法。
[項目7] AT2Rアゴニストを、レニン−アンジオテンシン系の調節不全を特徴とする病態の処置を必要とする哺乳動物に投与する、項目1に記載の方法。
[項目8] 病態が、高血圧、腎障害、腎疾患、心血管疾患、およびメタボリックシンドロームから成る群より選択される、項目7に記載の方法。
[項目9] AT2Rアゴニストを、in vivoで翻訳されて薬物を産生するmRNAを導入することにより投与する、項目1に記載の方法。
[項目10] AT2Rアゴニストを、AT1Rの過剰活性化を特徴とする病態の処置を必要とする哺乳動物に投与する、項目1に記載の方法。
[項目11] 病態が、腎障害、高血圧、およびメタボリックシンドロームから成る群より選択される、項目10に記載の方法。
[項目12] アゴニストを、実験室での研究用にAT2R受容体を活性化するための試薬として用いる、項目1に記載の方法。
[項目13] アゴニストを、AT2R活性化因子によって活性化または発現され得るmiRNAまたはタンパク質の活性化不足を特徴とする病態の処置を必要とする哺乳動物に投与する、項目1に記載の方法。
[項目14] アゴニストを、AT2Rの発現不足を特徴とする病態の処置を必要とする哺乳動物に投与する、項目1に記載の方法。
[項目15] さらなる安定性のためにアゴニストをペグ化する、項目1に記載の方法。
[項目16] アゴニストを、in vivoで発現して該アゴニストを産生する遺伝子配列または単離核酸を、ウイルスベクターを介して細胞に導入することにより投与する、項目1に記載の方法。
[項目17] アゴニストを、D1様受容体のAT2R介在活性化を刺激してマイクロ流体シミュレーション系におけるナトリウム排出を調節するための試薬として用いる、項目1に記載の方法。
[項目18] アゴニストを、実験室での研究用にAT1受容体の選択的阻害を可能にするための試薬として用いる、項目2に記載の方法。
[項目19] アゴニストを、in vivoで翻訳されて該アゴニストを産生するmRNAを導入することにより投与する、項目2に記載の方法。
[項目20] さらなる安定性のためにアゴニストをペグ化する、項目2に記載の方法。
[項目21] アゴニストを、in vivoで発現して該アゴニストを産生する遺伝子配列または単離核酸を、ウイルスベクターを介して細胞に導入することにより投与する、項目2に記載の方法。
[項目22] アゴニストを、糖尿病およびメタボリックシンドロームのような高血糖を特徴とする病態に対して投与する、項目1に記載の方法。
[項目23] 細胞がin vivoにある、項目1または2に記載の方法。
[項目24] 式:A1−A2−A3−A4−A5−A6、
式中:
A1は、Lysであり
A2は、Pro、3Hyp、または4Hypであり
A3は、LeuまたはIleであり
A4は、Lysであり
A5は、Pro、3Hyp、または4Hypであり、そして
A6は、Trpである、
に相当するアミノ酸配列を含むポリペプチドを含む、医薬組成物。
[項目25] 式:A1−A2−A3−A4−A5−A6、
式中:
A1は、Lysであり
A2は、Pro、3Hyp、または4Hypであり
A3は、LeuまたはIleであり
A4は、Lysであり
A5は、Pro、3Hyp、または4Hypであり、そして
A6は、Trpである、
に相当するアミノ酸配列から本質的に成るポリペプチドを含む、医薬組成物。
[項目26] 式:A1−A2−A3−A4−A5−A6、
式中:
A1は、Lysであり
A2は、Pro、3Hyp、または4Hypであり
A3は、LeuまたはIleであり
A4は、Lysであり
A5は、Pro、3Hyp、または4Hypであり、そして
A6は、Trpである、
に相当するアミノ酸配列から成るポリペプチドを含む、医薬組成物。
[項目27] ポリペプチドが、AT2R受容体を発現する細胞に投与したときにAT2Rアゴニスト活性を有する、項目24〜26のいずれか1項に記載の医薬組成物。
[項目28] A2がProである場合、A5は3Hypまたは4Hypであり;あるいは
A5がProである場合、A2は3Hypまたは4Hypである、
項目24〜26のいずれか1項に記載の医薬組成物。
[項目29] 凍結乾燥されている、項目24〜26のいずれか1項に記載の医薬組成物。
[項目30] 医薬的に許容されるキャリヤーをさらに含む、項目24〜26のいずれか1項に記載の医薬組成物。
両方を有する神経細胞株である。この細胞株をラパマイシンで処理すると、MCL−1発現は低減した。ラパマイシンによる処理後にこの細胞株にNP−6AKアゴニストを加えると、MCL−1発現を回復させることができた。NP−6AKアゴニストのみを300nMの濃度で加えると、これらの細胞はMCL−1発現において2倍の増大を示した。図2参照。
AngIIの天然リガンド(300nM)での処理と比較して、30%を超える細胞生存度の増大がもたらされた。300nMのCGP42112Aでの処理と比較して、NP−6AKアゴニストで処理した細胞は、70%をこえる生存の増大を示した。AngIIまたはCGP42112Aでの処理は、細胞をAT2RアンタゴニストのPD123319で処理したときに得られた結果と比較して、より有害であった。NP−6AKアゴニストによるAT2R活性化は細胞生存を促進するが、他のリガンドによるAT2R活性化は細胞生存に有害である。これらの結果は、MTS細胞増殖アッセイ(Biovision
Inc.、カリフォルニア州ミルピタス)を用いて評価した。
に援用する。
参考文献
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Claims (30)
- AT2Rタンパク質を発現する細胞において、AT2Rタンパク質を活性化する方法であって、
式:A1−A2−A3−A4−A5−A6、
式中:
A1は、Lysであり
A2は、Pro、3Hyp、または4Hypであり
A3は、LeuまたはIleであり
A4は、Lysであり
A5は、Pro、3Hyp、または4Hypであり、そして
A6は、Trpである、
に相当するアミノ酸配列を含むAT2Rアゴニストの有効量を該細胞に提供することを含む、前記方法。 - AT2Rタンパク質を発現する細胞において、AT1Rタンパク質を阻害する方法であって、
式:A1−A2−A3−A4−A5−A6、
式中:
A1は、Lysであり
A2は、Pro、3Hyp、または4Hypであり
A3は、LeuまたはIleであり
A4は、Lysであり
A5は、Pro、3Hyp、または4Hypであり、そして
A6は、Trpである、
に相当するアミノ酸配列を含むAT2Rアゴニストの有効量を該細胞に提供することを含む、前記方法。 - AT2Rの活性化不足、またはMTOR、NHE6、ErbB3、一酸化窒素合成酵素、MCL−1、およびプロスタグランジン12−IPから成る群より選択されるAT2Rの下流エフェクターの不十分な活性もしくは産生、を特徴とする病態の処置を必要とする哺乳動物にアゴニストを投与する、請求項1に記載の方法。
- 病態が、糖尿病、ErbB3の機能不全に関与するがん、および高血圧から成る群より選択される、請求項3に記載の方法。
- AT2Rアゴニストを、自閉症、ALS、アルツハイマー病、パーキンソン病、筋ジストロフィー、およびハンチントン病から成る群より選択される神経学的病態の処置を必要とする哺乳動物に投与する、請求項1に記載の方法。
- AT2Rアゴニストを、脊髄損傷、外傷性脳損傷、および脳病変から成る群より選択される損傷の処置を必要とする哺乳動物に投与する、請求項1に記載の方法。
- AT2Rアゴニストを、レニン−アンジオテンシン系の調節不全を特徴とする病態の処置を必要とする哺乳動物に投与する、請求項1に記載の方法。
- 病態が、高血圧、腎障害、腎疾患、心血管疾患、およびメタボリックシンドロームから成る群より選択される、請求項7に記載の方法。
- AT2Rアゴニストを、in vivoで翻訳されて薬物を産生するmRNAを導入す
ることにより投与する、請求項1に記載の方法。 - AT2Rアゴニストを、AT1Rの過剰活性化を特徴とする病態の処置を必要とする哺乳動物に投与する、請求項1に記載の方法。
- 病態が、腎障害、高血圧、およびメタボリックシンドロームから成る群より選択される、請求項10に記載の方法。
- アゴニストを、実験室での研究用にAT2R受容体を活性化するための試薬として用いる、請求項1に記載の方法。
- アゴニストを、AT2R活性化因子によって活性化または発現され得るmiRNAまたはタンパク質の活性化不足を特徴とする病態の処置を必要とする哺乳動物に投与する、請求項1に記載の方法。
- アゴニストを、AT2Rの発現不足を特徴とする病態の処置を必要とする哺乳動物に投与する、請求項1に記載の方法。
- さらなる安定性のためにアゴニストをペグ化する、請求項1に記載の方法。
- アゴニストを、in vivoで発現して該アゴニストを産生する遺伝子配列または単離核酸を、ウイルスベクターを介して細胞に導入することにより投与する、請求項1に記載の方法。
- アゴニストを、D1様受容体のAT2R介在活性化を刺激してマイクロ流体シミュレーション系におけるナトリウム排出を調節するための試薬として用いる、請求項1に記載の方法。
- アゴニストを、実験室での研究用にAT1受容体の選択的阻害を可能にするための試薬として用いる、請求項2に記載の方法。
- アゴニストを、in vivoで翻訳されて該アゴニストを産生するmRNAを導入することにより投与する、請求項2に記載の方法。
- さらなる安定性のためにアゴニストをペグ化する、請求項2に記載の方法。
- アゴニストを、in vivoで発現して該アゴニストを産生する遺伝子配列または単離核酸を、ウイルスベクターを介して細胞に導入することにより投与する、請求項2に記載の方法。
- アゴニストを、糖尿病およびメタボリックシンドロームのような高血糖を特徴とする病態に対して投与する、請求項1に記載の方法。
- 細胞がin vivoにある、請求項1または2に記載の方法。
- 式:A1−A2−A3−A4−A5−A6、
式中:
A1は、Lysであり
A2は、Pro、3Hyp、または4Hypであり
A3は、LeuまたはIleであり
A4は、Lysであり
A5は、Pro、3Hyp、または4Hypであり、そして
A6は、Trpである、
に相当するアミノ酸配列を含むポリペプチドを含む、医薬組成物。 - 式:A1−A2−A3−A4−A5−A6、
式中:
A1は、Lysであり
A2は、Pro、3Hyp、または4Hypであり
A3は、LeuまたはIleであり
A4は、Lysであり
A5は、Pro、3Hyp、または4Hypであり、そして
A6は、Trpである、
に相当するアミノ酸配列から本質的に成るポリペプチドを含む、医薬組成物。 - 式:A1−A2−A3−A4−A5−A6、
式中:
A1は、Lysであり
A2は、Pro、3Hyp、または4Hypであり
A3は、LeuまたはIleであり
A4は、Lysであり
A5は、Pro、3Hyp、または4Hypであり、そして
A6は、Trpである、
に相当するアミノ酸配列から成るポリペプチドを含む、医薬組成物。 - ポリペプチドが、AT2R受容体を発現する細胞に投与したときにAT2Rアゴニスト活性を有する、請求項24〜26のいずれか1項に記載の医薬組成物。
- A2がProである場合、A5は3Hypまたは4Hypであり;あるいは
A5がProである場合、A2は3Hypまたは4Hypである、
請求項24〜26のいずれか1項に記載の医薬組成物。 - 凍結乾燥されている、請求項24〜26のいずれか1項に記載の医薬組成物。
- 医薬的に許容されるキャリヤーをさらに含む、請求項24〜26のいずれか1項に記載の医薬組成物。
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WO2019238962A1 (en) * | 2018-06-14 | 2019-12-19 | University College Cork - National University Of Ireland, Cork | Peptide for disease treatment |
WO2020000469A1 (zh) * | 2018-06-29 | 2020-01-02 | 深圳市博奥康生物科技有限公司 | 促进 at2r 蛋白过表达的重组载体及其构建方法 |
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EP3220940B1 (en) | 2021-07-21 |
RU2017121091A (ru) | 2018-12-19 |
JP6934814B2 (ja) | 2021-09-15 |
AU2021221858A1 (en) | 2021-09-23 |
AU2015349863A1 (en) | 2017-06-01 |
US20170304390A1 (en) | 2017-10-26 |
CA2968053A1 (en) | 2016-05-26 |
IL252191A0 (en) | 2017-07-31 |
RU2721241C2 (ru) | 2020-05-18 |
RU2017121091A3 (ja) | 2019-06-05 |
US10105411B2 (en) | 2018-10-23 |
MX2017006491A (es) | 2018-02-13 |
IL252191B (en) | 2022-03-01 |
WO2016081733A3 (en) | 2016-07-28 |
US20190000916A1 (en) | 2019-01-03 |
ES2892957T3 (es) | 2022-02-07 |
EP3220940A4 (en) | 2018-10-03 |
US10675324B2 (en) | 2020-06-09 |
JP2017536415A (ja) | 2017-12-07 |
EP3220940A2 (en) | 2017-09-27 |
WO2016081733A2 (en) | 2016-05-26 |
AU2015349863B2 (en) | 2021-09-09 |
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