JP6517692B2 - 細胞透過性ペプチド、それを含んだコンジュゲート、及びそれを含んだ組成物 - Google Patents
細胞透過性ペプチド、それを含んだコンジュゲート、及びそれを含んだ組成物 Download PDFInfo
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- JP6517692B2 JP6517692B2 JP2015532967A JP2015532967A JP6517692B2 JP 6517692 B2 JP6517692 B2 JP 6517692B2 JP 2015532967 A JP2015532967 A JP 2015532967A JP 2015532967 A JP2015532967 A JP 2015532967A JP 6517692 B2 JP6517692 B2 JP 6517692B2
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- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
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- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
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- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
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- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
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- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
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Description
(1)疎水性:ノルロイシン、met、ala、val、leu、ile;
(2)中性親水性:cys、ser、thr;
(3)酸性:asp、glu;
(4)塩基性:asn、gln、his、lys、arg;
(5)鎖方向に影響を及ぼす残基:gly、pro;及び
(6)芳香族:trp、tyr、phe。
配列番号2ないし配列番号178のペプチドを、従来公知の固相ペプチド合成法によって製造した。具体的には、ペプチドは、ASP48S(Peptron、Inc.,大韓民国大田所在)を利用して、Fmoc固相合成法(SPPS:solid phase peptide synthesis)を介して、C末端からアミノ酸を一つずつカップリングすることによって合成した。次のように、ペプチドのC末端の最初のアミノ酸が樹脂に付着したものを使用した。例えば、次の通りである:
NH2−Ala−2−chloro−Trityl Resin
NH2−Arg(Pbf)−2−chloro−Trityl Resin
NH2−Lys(Boc)−2−chloro−Trityl Resinに保護されたアミノ酸(8当量)と、カップリング試薬HBTU(8当量)/HOBt(8当量)/NMM(16当量)とをDMFに溶解させて添加した後、常温で2時間反応させ、DMF、MeOH、DMFの順に洗浄した。
20%のDMF中のピペリジン(piperidine in DMF)を加え、常温で5分間2回反応させ、DMF、MeOH、DMFの順に洗浄した。
(1)FITC−CPPコンジュゲートの製造
配列番号2ないし配列番号178のペプチドをFITCと接合させたコンジュゲートを、次のように製造した。例えば、配列番号1のpep1とFITCとのコンジュゲート、すなわち、FITC−linker−pep1を次のように製造した。
前記実施例1のように、ペプチド基本骨格(NH2−E(OtBu)−A−R(Pbf)−P−A−L−L−T(tBu)−S(tBu)−R(Pbf)L−R(Pbf)−F−I−P−K(Dde)−2−chloro−trityl樹脂)を製造した。製造されたペプチド基本骨格のC−termに、FITCを選択的に導入するために、N−termをBocで保護した。その後、ジ−tert−ブチルジカーボネート(30当量)とDIPEA(30当量)とをDMFに溶かして添加した後、常温で2時間反応させ、DMF、MeOH、DMFの順に洗浄した。その結果、Boc−E(OtBu)−A−R(Pbf)−P−A−L−L−T(tBu)−S(tBu)−R(Pbf)L−R(Pbf)−F−I−P−K(Dde)−2−chloro−trityl樹脂を得た。その後、C−term Kの残基にFITCを付けるために、2% DMF中のヒドラジン(hydrazine in DMF)を処理し、C−term Lysの残基保護基であるDdeを除去した。その結果、Boc−E(OtBu)−A−R(Pbf)−P−A−L−L−T(tBu)−S(tBu)−R(Pbf)L−R(Pbf)−F−I−P−K(NH2)−2−chloro−trityl樹脂を得た。その後、FITC(8当量)とDIPEA(16当量)とをDMFに溶かして添加した後、常温で2時間反応させ、DMF、MeOH、DMFの順に洗浄した。その結果、Boc−E(OtBu)−A−R(Pbf)−P−A−L−L−T(tBu)−S(tBu)−R(Pbf)L−R(Pbf)−F−I−P−K(FITC)−2−chloro−trityl樹脂を得た。前記合成が完了したペプチド樹脂に、TFA/TIS/H2O=95/2.5/2.5を加え、ペプチドを樹脂から分離した。得られた混合物にクーリングジエチルエーテルを加えた後、遠心分離して得られたペプチドを沈澱させた。その後、Prep−HPLCで精製した後、分析的(analytical)HPLCで純度を確認し、LC/MSで分子量を確認した。その結果として得られた物質がpep1−FITCであるということが立証された。その後、乾燥を行った。
1.フェロセンカルボン酸(ferrocenecarboxylic)−CPPコンジュゲートの製造
カップリングのためにNH2−Lys(Dde)−2−クロロ−トリチル樹脂に保護されたアミノ酸(8当量)と、カップリング試薬HBTU(8当量)/HOBt(8当量)/NMM(16当量)とをDMFに溶かして添加した後、常温で2時間反応させ、DMF、MeOH、DMFの順に洗浄した。その後、Fmoc脱保護(deprotection)のために、20% DMF中のピペリジン(piperidine in DMF)を加え、常温で5分間2回反応させ、DMF、MeOH、DMFの順に洗浄した。前記反応を反復して行い、ペプチド基本骨格(NH2−E(OtBu)−A−R(Pbf)−P−A−L−L−T(tBu)−S(tBu)−R(Pbf)L−R(Pbf)−F−I−P−K(Dde)−2−クロロ−トリチル樹脂)を作った。ここに、2% DMF中のヒドラジン(hydrazine in DMF)を処理し、C末端Lysの残基保護基のDdeを除去した。その後、フェロセンカルボン酸(ferrocenecarboxylic acid)(Sigma Aldrich cat.#46264、16当量)と、カップリング試薬HBTU(16当量)/HOBt(16当量)/NMM(32当量)とをDMFに溶かして添加した後、常温で2時間反応させ、DMF、MeOH、DMFの順に洗浄した。合成が完了したペプチド樹脂に、TFA/TIS/H2O=95/2.5/2.5を加え、ペプチドを樹脂から分離した。得られた混合物に、クーリングジエチルエーテル(cooling diethyl ether)を加えた後、遠心分離して得られたペプチドを沈澱させた。これをHPLCで精製した後、MSで確認して凍結乾燥した。
(1)HeLa細胞株での細胞透過能試験
細胞株培養
ATCCから得たHeLa細胞株をMEM(minimum essential medium)に、10%ウシ胎児血清(Invitrogen、米国)、Earle's salts、non-essential amino acids、ピルピン酸ナトリウム及び100μg/mlペニシリン及び100units/mlストレプトマイシンを添加し、37℃、5% CO2培養器で培養した。
前記細胞株に、本発明の配列番号2ないし178のペプチド、pep(CPP)を処理し、controlとuptake程度を比較するために、流細胞分析器(flow cytometry)及び共焦点顕微鏡(confoca lmicroscopy)の分析を実施した。
細胞株培養
ヒト肝細胞癌の細胞株であるHuh7(human hepatocellularcarcinoma cell lien)の浮遊細胞株を使用した(ATCC(American Typ eCell Culture)から購入)。Huh7細胞株は、RPMI 1640培地を使用する。培地には、10%ウシ胎児血清(Invitrogen、米国)、100μg/mlペニシリン及び100units/ストレプトマイシンを添加し、37℃、5% CO2培養器で培養した。
ペプチドの細胞浸透能を調べるために、配列番号2ないし配列番号178のペプチドを処理したHuh7細胞株において、流細胞分析を行った。分析方法は、前記(1)のHela細胞株分析に記載された通りである。分析結果は、図30ないし図51に示した。
細胞株培養
ヒトTリンパ球細胞株Jurkat(human T−cell leukemia cell line)の浮遊細胞株を使用した(ATCC(American Type Cell Culture)から購入)。Jurkat細胞株は、RPMI 1640培地を使用する。培地には、10%ウシ胎児血清(Invitrogen、米国)、100μg/mlペニシリン及び100units/mlストレプトマイシンを添加し、37℃、5% CO2培養器で培養した。
ペプチドの細胞浸透能を調べるために、配列番号2ないし配列番号178のペプチドを処理したヒトTリンパ球細胞株で流細胞分析を行った。分析方法は、前記(1)のHela細胞株分析に記載された通りようである。分析結果は、図52ないし図69に示した。
一方、前記実施例4(1)で培養されたHela細胞株を96−ウェルプレートに分注し、培地に10%ウシ胎児血清(Invitrogen、米国)、100μg/mlペニシリン及び100units/mlストレプトマイシンを添加し、37℃、5% CO2培養器で12時間培養した。PBS洗浄後、MEM(minimum essential medium)で1時間のstarvationを行わせた。各運搬ペプチド20μMで処理し、37℃で24時間培養した後、MTT assay方法を利用して、細胞生存率及び毒性を分析した。その結果は、図70ないし図86に示されている通りである。
Claims (20)
- 細胞透過性運搬ペプチド及び有効成分のコンジュゲートであって、前記運搬ペプチドは、配列番号2〜配列番号79、配列番号91、配列番号92、配列番号104、配列番号105、配列番号110及び配列番号121のうちいずれか一つのアミノ酸配列から成るペプチドである、前記コンジュゲート。
- 前記有効成分は、タンパク質、核酸、ペプチド、脂質、糖脂質、ミネラル、糖、ナノ粒子、生物学的製剤、造影物質、薬物及び化学物質のうちから選択される一つ以上である、請求項1に記載のコンジュゲート。
- 前記運搬ペプチドと有効成分は、共有結合によって連結され、リンカーによって選択的に媒介されて連結される、請求項1に記載のコンジュゲート。
- 前記運搬ペプチドと有効成分は、非共有結合によって連結される、請求項1に記載のコンジュゲート。
- 前記有効成分は、タンパク質またはペプチドである、請求項2に記載のコンジュゲート。
- 前記有効成分は、サイトカイン、抗体、抗体断片、治療用酵素、可溶性受容体またはリガンドである、請求項5に記載のコンジュゲート。
- 前記造影物質は、放射線非透過性造影物質、常磁性造影物質、超常磁性造影物質及びCT造影物質からなる群から選択される、請求項2に記載のコンジュゲート。
- 前記造影物質は鉄に基づく、請求項2に記載のコンジュゲート。
- 前記造影物質はフェロセンカルボン酸である、請求項8に記載のコンジュゲート。
- 請求項1〜9のうちいずれか1項に記載のコンジュゲートを含む造影剤。
- 細胞を造影するためのものである、請求項10に記載の造影剤。
- 前記細胞は幹細胞である、請求項11に記載の造影剤。
- 有効成分として、請求項1〜9のうちいずれか1項に記載のコンジュゲートを含む組成物。
- 前記有効成分は、疾病の治療または予防のための有効成分であり、前記組成物は、医薬組成物である、請求項13に記載の組成物。
- 前記有効成分は、機能性化粧品の有効成分であり、前記組成物は、化粧品組成物である、請求項13に記載の組成物。
- 前記有効成分は、機能性健康食品の有効成分であり、前記組成物は、健康食品組成物である、請求項13に記載の組成物。
- 細胞透過性ペプチドであって、前記ペプチドは、配列番号2〜配列番号79、配列番号91、配列番号92、配列番号104、配列番号105、配列番号110及び配列番号121のうちいずれか1つの配列から成る、細胞透過性ペプチド。
- 請求項17に記載のペプチドをコードするポリヌクレオチド。
- 請求項18に記載のポリヌクレオチドを含むベクター。
- 請求項19に記載のベクターを含む形質転換細胞。
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US11844845B2 (en) | 2023-12-19 |
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