JP2022552993A - 血液脳関門透過能を有するペプチド核酸複合体及びこれを含む組成物 - Google Patents
血液脳関門透過能を有するペプチド核酸複合体及びこれを含む組成物 Download PDFInfo
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Abstract
Description
[構造式(1)]
[A≡C(+)]
前記構造式(1)において、
Aは、目的とする遺伝子と結合可能な配列、又は目的とする遺伝子配列を有する生物活性核酸(Bioactive Nucleic Acid)であり、
Cは、生物活性核酸と結合可能なキャリアペプチド核酸(Carrier Peptide Nucleic Acid)であり;
‘≡’は、生物活性核酸とキャリアペプチド核酸との相補的な結合を意味し、
Aで表される生物活性核酸は、ペプチド核酸(Peptide Nucleic Acid)であって、全体的に陰電荷を有し、
C(+)で表されるキャリアペプチド核酸は、全体的に陽電荷を有し、
A≡C(+)で表される構造式(1)の核酸複合体は、全体的に陽電荷を有し、
前記キャリアペプチド核酸は、キャリアペプチド核酸が全体的に陽電荷を帯びるように1個以上のガンマ或いはアルファバックボーン修飾ペプチド核酸単量体を一つ以上含み、前記ガンマ或いはアルファバックボーン修飾ペプチド核酸単量体は、陽電荷を有するアミノ酸を有する単量体が、陰電荷を有するアミノ酸を有する単量体に比べてより多く含まれ、全体的なキャリアペプチド核酸の電荷が陽性になることを特徴とする。
[A≡C(+)]
前記構造式(1)において、
Aは、目的とする遺伝子と結合可能な配列、又は目的とする遺伝子配列を有する生物活性核酸(Bioactive Nucleic Acid)であり、
Cは、生物活性核酸と結合可能なキャリアペプチド核酸(Carrier Peptide Nucleic Acid)であり;
‘≡’は、生物活性核酸とキャリアペプチド核酸との相補的な結合を意味し、
Aで表される生物活性核酸は、ペプチド核酸(Peptide Nucleic Acid)であって、全体的に陰電荷を有し、
C(+)で表されるキャリアペプチド核酸は、全体的に陽電荷を有し、
A≡C(+)で表される構造式(1)の核酸複合体は、全体的に陽電荷を有し、
前記キャリアペプチド核酸は、キャリアペプチド核酸が全体的に陽電荷を帯びるように1個以上のガンマ或いはアルファバックボーン修飾ペプチド核酸単量体を一つ以上含み、前記ガンマ或いはアルファバックボーン修飾ペプチド核酸単量体は、陽電荷を有するアミノ酸を有する単量体が、陰電荷を有するアミノ酸を有する単量体に比べてより多く含まれ、全体的なキャリアペプチド核酸の電荷が陽性になることを特徴とする。
[mA≡mC(+)]
前記構造式(2)において、
‘m’は、生物活性核酸とキャリアペプチド核酸のエンドソーム脱出(endosome escape)を助ける物質を意味する。
[A≡C(+)]
前記構造式(1)において、
Aは、目的とする遺伝子と結合可能な配列、又は目的とする遺伝子配列を有する生物活性核酸(Bioactive Nucleic Acid)であり、
Cは、生物活性核酸と結合可能なキャリアペプチド核酸(Carrier Peptide Nucleic Acid)であり;
‘≡’は、生物活性核酸とキャリアペプチド核酸との相補的な結合を意味し、
Aで表される生物活性核酸は、ペプチド核酸(Peptide Nucleic Acid)であって、全体的に陰電荷を有し、
C(+)で表されるキャリアペプチド核酸は、全体的に陽電荷を有し、
A≡C(+)で表される構造式(1)の核酸複合体は、全体的に陽電荷を有し、
前記キャリアペプチド核酸は、キャリアペプチド核酸が全体的に陽電荷を帯びるように、1個以上のガンマ或いはアルファバックボーン修飾ペプチド核酸単量体を一つ以上含み、前記ガンマ或いはアルファバックボーン修飾ペプチド核酸単量体は、陽電荷を有するアミノ酸を有する単量体が、陰電荷を有するアミノ酸を有する単量体に比べてより多く含まれ、全体的なキャリアペプチド核酸の電荷が陽性になることを特徴とする。
Claims (22)
- 下記構造式(1)の構造を有する核酸複合体を含む血液脳関門透過用組成物。
[構造式(1)]
[A≡C(+)]
前記構造式(1)において、
Aは、目的とする遺伝子と結合可能な配列、又は目的とする遺伝子配列を有する生物活性核酸(Bioactive Nucleic Acid)であり、
Cは、生物活性核酸と結合可能なキャリアペプチド核酸(Carrier Peptide Nucleic Acid)であり;
‘≡’は、生物活性核酸とキャリアペプチド核酸との相補的な結合を意味し、
Aで表される生物活性核酸は、ペプチド核酸(Peptide Nucleic Acid)であって、全体的に陰電荷を有し、
C(+)で表されるキャリアペプチド核酸は、全体的に陽電荷を有し、
A≡C(+)で表される構造式(1)の核酸複合体は、全体的に陽電荷を有し、
前記キャリアペプチド核酸は、キャリアペプチド核酸が全体的に陽電荷を帯びるように1個以上のガンマ或いはアルファバックボーン修飾ペプチド核酸単量体を一つ以上含み、前記ガンマ或いはアルファバックボーン修飾ペプチド核酸単量体は、陽電荷を有するアミノ酸を有する単量体が、陰電荷を有するアミノ酸を有する単量体に比べてより多く含まれ、全体的なキャリアペプチド核酸の電荷が陽性になることを特徴とする。 - 前記生物活性核酸又はキャリアペプチド核酸は、それぞれの核酸の5’末端又は3’末端に、エンドソーム脱出を助ける物質がさらに結合していることを特徴とする、請求項1に記載の組成物。
- 前記エンドソーム脱出を助ける物質は、ペプチド、脂質ナノ物質(lipid nanoparticles)、接合体ナノ物質(polyplex nanoparticles)、高分子ナノ球(polymer nanospheres)、無機物ナノ物質(inorganic nanoparticles)、陽イオン脂質ナノ物質(cationic lipid-based nanoparticles)、陽イオン高分子(cationic polymer)及びpH感応高分子(pH sensitive polymers)からなる群から選ばれるいずれか一つ以上であることを特徴とする、請求項2に記載の組成物。
- 前記ペプチドは、GLFDIIKKIAESF(配列番号5)又はヒスチジン(10)であることを特徴とする、請求項3に記載の組成物。
- 前記生物活性核酸は、核酸の5’末端又は3’末端に疾患の治療又は診断用物質がさらに結合していることを特徴とする、請求項1に記載の組成物。
- 前記生物活性核酸とキャリアペプチド核酸はそれぞれ、2~50個の核酸単量体を含むことを特徴とする、請求項1に記載の組成物。
- 前記キャリアペプチド核酸は、前記生物活性核酸と塩基配列の一部或いは全部が相補的な配列で構成されることを特徴とする、請求項1に記載の組成物。
- 前記一部が相補的な配列で構成されるキャリアペプチド核酸は、一つ以上のユニバーザル塩基を含むことを特徴とする、請求項7に記載の組成物。
- 前記陽電荷を有するアミノ酸は、リジン(Lysine,Lys,K)、アルギニン(Arginine,Arg,R)、ヒスチジン(Histidine,His,H)、ジアミノ酪酸(Diamino butyric acid,DAB)、オルニチン(Ornithine,Orn)及びアミノ酸類似体からなる群から選ばれる一つ以上であることを特徴とする、請求項1に記載の組成物。
- 前記陰電荷を有するアミノ酸はグルタミン酸(Glu,E)、アスパラギン酸(Asp,D)又はアミノ酸類似体であることを特徴とする、請求項1に記載の組成物。
- 前記生物活性核酸及びキャリアペプチド核酸は、それぞれの核酸の5’-方向性及び3’-方向性によって平行(parallel)又は逆平行(antiparallel)に結合していることを特徴とする、請求項1に記載の組成物。
- 前記生物活性核酸及びキャリアペプチド核酸の結合力(融解温度、melting temperature、Tm)は、生物活性核酸と生物活性核酸の目的とする遺伝子との結合力よりも低いことを特徴とする、請求項1に記載の組成物。
- 前記生物活性核酸とキャリアペプチド核酸は、平行結合(Parallel binding)又は部分特異結合(Partial specific binding)することにより、生物活性核酸及びキャリアペプチド核酸の結合力(melting temperature,Tm)が、生物活性核酸と生物活性核酸の目的とする遺伝子との結合力よりも低いことを特徴とする、請求項12に記載の組成物。
- 前記キャリアペプチド核酸がリンカー、ユニバーザル塩基(universal base)及び生物活性核酸の対応する塩基と相補的でない塩基を有するペプチド核酸塩基から選択された一つ以上のペプチド核酸塩基を有することにより、生物活性核酸及びキャリアペプチド核酸の結合力(融解温度、melting temperature、Tm)が、生物活性核酸と生物活性核酸の目的とする遺伝子との結合力よりも低いことを特徴とする、請求項12に記載の組成物。
- 前記生物活性核酸とキャリアペプチド核酸との結合力の調節により、生物活性核酸とキャリアペプチド核酸の分離時点、及び生物活性核酸と生物活性核酸の目的とする遺伝子の結合時点の調節が可能になることを特徴とする、請求項12に記載の組成物。
- 前記ユニバーザル塩基(universal base)は、アデニン(adenine)、グアニン(guanine)、シトシン(cytosine)、チミン(thymine)、ウラシル(Uracil)などの天然塩基と選択性無しで結合し、相補的な結合力よりも低い結合力を有する塩基としてイノシンPNA(inosine PNA)、インドールPNA(indole PNA)、ニトロインドールPNA(nitroindole PNA)及び無塩基(abasic)からなる群から選ばれる一つ以上であることを特徴とする、請求項14に記載の組成物。
- 疎水性残基(hydrophobic moiety)、親水性残基(hydrophilic moiety)、標的抗原特異的抗体、アプタマー、クエンチャー、蛍光マーカー及び発光マーカーからなる群から選ばれる一つ以上の物質が生物活性核酸及び/又はキャリアペプチド核酸に結合していることを特徴とする、請求項1に記載の組成物。
- 疎水性残基(hydrophobic moiety)、親水性残基(hydrophilic moiety)、標的抗原特異的抗体、アプタマー、クエンチャー、蛍光マーカー及び発光マーカーからなる群から選ばれる一つ以上の物質と生物活性核酸及び/又はキャリアペプチド核酸との結合は、単純共有結合又はリンカー媒介の共有結合であることを特徴とする、請求項17に記載の組成物。
- 前記疾患は、脳疾患であることを特徴とする、請求項5に記載の組成物。
- 前記脳疾患は、アルツハイマー病、パーキンソン病、ハンチントン病、ルーゲーリック病、クロイツフェルト・ヤコブ病、ニーマン・ピック病、脳卒中、中風、認知症、血栓症、塞栓症、一過性虚血発作、小梗塞、脳溢血、脳梗塞、頭部損傷、脳循環代謝障害、脳機能昏睡、脳癌及び脳腫瘍からなる群から選ばれることを特徴とする、請求項19に記載の組成物。
- 脳疾患の予防又は治療用医薬組成物であることを特徴とする、請求項19に記載の組成物。
- 脳疾患の診断用組成物であることを特徴とする、請求項19に記載の組成物。
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