JP4773695B2 - マイクロ波利用のペプチド合成 - Google Patents
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Description
本発明は、固相ペプチド合成(SPPS)に関するものであり、詳しくは、SPPSのためのマイクロ波利用技術に関するものである。
20世紀初めには、合成製造されたペプチドによって、化学構造と生物活性との関係に関する研究を大いに促進できるという科学研究における新しい概念が誕生した。それまでは、ペプチドとそれらの生物学的機能との間の構造活性関係に関する研究は、精製された天然のペプチドを用いて行われてきた。しかしながら、その初期のペプチド精製のための溶液ベースの技術では、例えば、生成物の収率が低い、不純物による汚染、手間がかかる、いくつかのペプチドの溶解性が予想できないというような問題に悩まされていた。20世紀前半の間は、いくつかの溶液ベースの合成技術では、公知の技術をそれらの限界まで用いることによって、一定の「難しい」ペプチドを製造できた。より高い収率及び純度でペプチドを得たいという需要が増加することにより、まず最初に、固相ペプチド合成(SPPS)と現在呼ばれている、1963年に示されたアミノ酸から直接ペプチドを合成するための画期的な技術が生まれた。
SPPSの基本原則は、カップリング相が完成したら切断及び精製することができる固相粒子にリンカー分子を介して固定される成長ポリペプチド鎖に対して、アミノ酸を段階的に添加することである。簡単に言えば、固相樹脂支持体及び出発アミノ酸は、リンカー分子を介して互いに付着する。そのような樹脂−リンカー−酸マトリクスは商業的に入手可能である(例えば、ドイツのダルムシュタットのMerck KGaAの関係会社であるEMD Biosciencesの商標であるCalbiochem;又は、ドイツのハイデルベルクにあるORPEGEN Pharma)。出発アミノ酸は、そのアミノ末端において化学基によって保護され、また化学側鎖保護基を有していてもよい。保護基は、遊離アミノ酸の非保護カルボキシル基と成長ペプチド鎖の脱保護α−アミノとの間での新しいペプチド結合の形成中に、不所望な反応又は有害な反応がα−アミノ基において起こるのを防ぐ。続いて、最後までカップリング結合させるためのペプチド鎖において、一連の化学的工程によりアミノ酸が脱保護され、次のアミノ酸が準備される。換言すれば、アミノ酸を「保護」することにより、不所望な副反応又は競争反応が防止され、アミノ酸を「脱保護」することにより、その官能基(単数又は複数)は所望の反応のために利用可能となる。
一の側面において、本発明は、ペプチドの固相合成のための方法であって:(a)固相樹脂に結合された第一アミノ酸を、保護第一化学基を除去することにより脱保護する工程;(b)第二アミノ酸上の化学基を活性化して、該第一アミノ酸とのカップリングのための第二アミノ酸を調製する工程;(c)該活性化第二アミノ酸を該脱保護第一アミノ酸にカップリングさせて、該第一アミノ酸及び該第二アミノ酸からペプチドを形成する工程;及び(d)マイクロ波のエネルギーを施用して、脱保護、活性化及びカップリングのサイクルを促進する工程を含む方法である。
本発明は、1つ以上のペプチドを固相合成するための装置及び方法であって、具体的には、マイクロ波エネルギーを利用してかかる方法を促進する装置及び方法である。
好ましい態様において、本発明は更に第四通路52も含み、第四通路52は、セル45を溶媒で洗い流すため、外部溶媒源(図6)とセル45との間を流体連絡している。図3に示すように、第四通路52には、セル45に溶媒を添加するためにスプレーヘッド53又はそれと等価な構造が含まれる。
更に、図6には、スプレーヘッド53とともに第四通路52も図示してある。図3に関して説明したように、第四通路52は、そのうちの3つは76,A,B及びCで示されている1つ以上の外部溶媒源と流体連絡している。2つの他の外部溶媒源77及び80は、任意に異なる流体の通路なので、別々に標識してある。
図6Aは、反応器45に隣接するバルブ系に関する更に詳細な説明である。特に、図6Aは、一連の三方バルブ111、112、113、114及び115と共に、一連の液体センサー106、107及び110を示している。これらのセンサーにしたがってバルブを操作すると、望ましいか又は必要な場合に、計量された量の液体を反応容器45に添加することができる。例えば、図6Aの方向で示されているバルブ111、113及び114により、反応容器45の中に直接延びている第二通路47のそれらの部分に対して、流体をバルブ86から直接流すことができる。別法として、バルブ111がバルブ112の方へと開放している場合、流体は、液体センサー107及び110に達するまで、バルブ111及び112を通って流れる。液体センサーは適切な又は所望な量の液体が含まれている場合に系に通知し、バルブ112の操作を変更することにより、これらの液体を、望まされるようにバルブ113、次いでバルブ114、更に次いで第二通路47、そして最終的にセル45の中に送達することができる。
特に好ましい態様において、本方法は、サイクルとサイクルとの間に、固相樹脂からペプチドを取り出すことなく、単一の容器において複数のアミノ酸を連続的に脱保護し、活性化し、そしてカップリングさせてペプチドにすることを含む。本発明のこの側面及び追加の側面は、図に関する考察によって理解される。
実験:
ペプチド:Asn−Gly−Val
-MW=288
規模=0.10mmol
用いた樹脂=Fmoc−Val−Wang樹脂
樹脂置換=樹脂1gあたり0.27×10−3モル
マイクロ波プロトコル:
このペプチドにおけるすべての反応に関して、マイクロ波出力は、はじめに50Wに設定し、次いで60℃未満の温度に保たれるように調節した。
切断:切断は、95%TFA及び5%H2Oを用いて90:00分間行った。
ペプチド:Gly−Asn−Ile−Tyr−Asp−Ile−Ala−Ala−Gln−Val
-MW=1062
規模=0.25mmol
用いた樹脂=Fmoc−Val−Wang樹脂
樹脂置換=樹脂1gあたり0.27×10−3モル
マイクロ波プロトコル:
このペプチドは、出力時間制御法によって合成した。
切断:切断は、95%TFA、2.5%H2O及び2.5%TISを用いて行った。
Claims (11)
- ペプチドの固相合成を促進する方法であって:
Na−9−フルオレニルメチルオキシカルボニル(Fmoc)及びNa−t−ブトキシカルボニル(Boc)からなる群から選択された組成物で保護され、固相樹脂粒子に結合された第一アミノ酸のα−アミノ基を、マイクロ波透過性容器において該保護され結合されたアミノ酸を脱保護性溶液と混合し、該混合したアミノ酸及び溶液にマイクロ波を照射することにより、脱保護する工程;
第二アミノ酸及び活性化溶液を該同一容器に添加し、該第二アミノ酸を活性化させる工程;
該同一容器中の組成物にマイクロ波を照射しながら、該第二アミノ酸を該第一アミノ酸にカップリングさせる工程;及び
サイクルとサイクルとの間に該同一のマイクロ波透過性容器からペプチドを取り出すことなく、該同一の容器において複数のアミノ酸を連続的に脱保護し、活性化し、そしてカップリングしてペプチドを形成する工程、
を含む方法。 - 脱保護工程、活性化工程、カップリング工程及び切断工程の任意の1つ以上の工程の間に容器を冷却して、マイクロ波エネルギーからの熱の蓄積により固相支持体又はペプチドが分解するのを防ぐ工程を含む、請求項1記載のペプチド合成方法。
- 3つ以上のアミノ酸に関して脱保護工程、活性化工程及びカップリング工程を連続して周期的に繰り返すことにより、所望のペプチドを合成することを含む、請求項1記載のペプチド合成方法。
- 複数の周期の間にペプチドを固相樹脂から又は容器から取り出すことなく、連続する脱保護工程、活性化工程、カップリング工程及び切断工程を単一反応器において実施することを含む、請求項1記載のペプチド合成方法。
- 更に、脱保護工程、活性化工程、カップリング工程及び切断工程の1つ以上の工程の間に、混合物を窒素気体により撹拌する工程を含む、請求項1記載のペプチド合成方法。
- アミノ酸の側鎖を脱保護することを含む、請求項1記載のペプチド合成方法。
- 該アミノ酸の該側鎖を、t−ブチルをベースとする側鎖保護基を除去するのに適する組成物で脱保護することを含む、請求項6記載のペプチド合成方法。
- 更に、カルボジイミド型のカップリング試薬を用いて、第二アミノ酸をin situで活性化させカップリングさせることを含む、請求項1記載のペプチド合成方法。
- 該同一容器内の組成物にマイクロ波を照射しながら第一アミノ酸に第二アミノ酸をカップリングさせる、請求項1記載のペプチド合成方法。
- 固相樹脂に結合されたペプチドを、該同一容器において切断性組成物と混合し、該組成物にマイクロ波を照射しながら、該結合ペプチドを該固相樹脂から切断する工程を含む、請求項1記載のペプチド合成方法。
- 更に、トリフルオロ酢酸から成り、保護基及びリンカーから生ずる反応性カルボニウムイオンを消失させるための複数の掃去剤を含有する切断性組成物を用いることを含む、請求項10記載のペプチド合成方法。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US10/604022 | 2003-06-23 | ||
US10/604,022 US7393920B2 (en) | 2003-06-23 | 2003-06-23 | Microwave-assisted peptide synthesis |
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EP (2) | EP1491552B1 (ja) |
JP (1) | JP4773695B2 (ja) |
AT (1) | ATE459415T1 (ja) |
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JP2005015483A (ja) * | 2003-06-23 | 2005-01-20 | Cem Corp | マイクロ波利用のペプチド合成 |
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Cited By (6)
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JP2005015483A (ja) * | 2003-06-23 | 2005-01-20 | Cem Corp | マイクロ波利用のペプチド合成 |
US8426560B2 (en) | 2003-06-23 | 2013-04-23 | Cem Corporation | Microwave-assisted peptide synthesis |
US8846862B2 (en) | 2003-06-23 | 2014-09-30 | Cem Corporation | Microwave-assisted peptide synthesis |
US9211522B2 (en) | 2003-06-23 | 2015-12-15 | Cem Corporation | Microwave-assisted peptide synthesis |
US9669380B2 (en) | 2003-06-23 | 2017-06-06 | Cem Corporation | Microwave-assisted peptide synthesis |
US10052607B2 (en) | 2003-06-23 | 2018-08-21 | Cem Corporation | Microwave-assisted peptide synthesis |
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