JP5497449B2 - 生体高分子およびポリペプチドの化学修飾方法 - Google Patents
生体高分子およびポリペプチドの化学修飾方法 Download PDFInfo
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- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
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- 150000003573 thiols Chemical class 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
- C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
- C07K1/1077—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
- A61K47/6435—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the peptide or protein in the drug conjugate being a connective tissue peptide, e.g. collagen, fibronectin or gelatin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/13—Labelling of peptides
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08H—DERIVATIVES OF NATURAL MACROMOLECULAR COMPOUNDS
- C08H1/00—Macromolecular products derived from proteins
- C08H1/06—Macromolecular products derived from proteins derived from horn, hoofs, hair, skin or leather
Description
好ましくは、生体高分子は、タンパク質、多糖、及びそれらの誘導体からなる群から選ばれる少なくとも一種を含む。
好ましくは、生体高分子はタンパク質である。
好ましくは、タンパク質は、ヒト、牛、豚、魚、又は植物に由来するタンパク質、あるいは遺伝子組み換えタンパク質である。
好ましくは、化学修飾は、分子間の架橋反応、又は分子内の架橋反応である。
好ましくは、化学修飾は、生体高分子又はポリペプチドへの官能基の導入である。
好ましくは、生体高分子の化学修飾のために使用される化合物は、炭酸エステル基、エポキシド基、エステル基、アミド基、又はジチオカルバミル基を有している化合物である。
好ましくは、縮合剤を用いて化学修飾を行う。
好ましくは、酸無水物、酸塩化物、又はエポキシドとの反応により化学修飾を行う。
好ましくは、有機フッ素化合物は、アルコール、ケトンである。
好ましくは、有機フッ素化合物は、2,2,2−トリフルオロエタノール、1,1,1,3,3,3-ヘキサフルオロ-2-プロパノール、又はヘキサフルオロアセトンである。
好ましくは、有機フッ素化合物は2,2,2−トリフルオロエタノールである。
本発明で用いる生体高分子(生体由来の高分子)は、本発明を実現可能である限りは特に規定はないが、好ましくはタンパク質、多糖、又はそれらの誘導体又は塩類である。タンパク質の場合は、球状、繊維状等のタンパク質のいずれでもよい。本発明でいう生体高分子には合成ポリペプチドも含まれる。生体高分子は、より好ましくは、コラーゲン、ゼラチン、アルブミン、ラミニン、カゼイン、フィブロイン、フィブリン、キトサン、フィブロネクチン、ビトロネクチン、ウロキナーゼ、トロンボモジュリン、アンチトロンビンIIIおよびヒアルロン酸エステルである。さらに好ましくは、コラーゲン、ゼラチン、アルブミン、カゼイン、フィブロインである。最も好ましくはコラーゲンまたはゼラチンである。タンパク質の由来は特に限定せず、ヒト、牛、豚、魚、および遺伝子組み換え体のいずれを用いても良い。遺伝子組み換え体としては、例えばEP0926543B,WO2004-085473号明細書、EP1398324A、EP1014176A、US6645712に記載のものを用いることができるがこれらに限定されるものではない。また、該生体高分子は部分的に加水分解されていてもよい。
また、化学修飾に用いる化合物として、酸無水物(例えば:2−N,N-ジエチルジチオカルバミルメチルー安息香酸無水物、3−N,N-ジエチルジチオカルバミルメチルー安息香酸無水物、4−N,N-ジエチルジチオカルバミルメチルー安息香酸無水物、2−ビニル安息香酸無水物、3−ビニル安息香酸無水物、4−ビニル安息香酸無水物)、酸塩化物(例えば:2−N,N-ジエチルジチオカルバミルメチルー安息香酸塩化物、3−N,N-ジエチルジチオカルバミルメチルー安息香酸塩化物、4−N,N-ジエチルジチオカルバミルメチルー安息香酸塩化物、2−ビニル塩化ベンゾイル、3−ビニル塩化ベンゾイル、4−ビニル塩化ベンゾイル)、エポキシドを用いることができる。
本発明において生体高分子と反応基質との混合温度は、溶液を均一に攪拌できる限り特に限定されないが、好ましくは0℃〜40℃であり、より好ましくは0℃〜30℃であり、より好ましくは3℃〜25℃であり、より好ましくは3℃〜15℃であり、さらに好ましくは3℃〜10℃であり、特に好ましくは3℃〜7℃である。
生体組織中への埋め込み部位として特に強度が求められる部位としては、例えば、骨、軟骨、心臓、血管などが挙げられる。
縮合剤として水溶性カルボジイミド(Water Soluble Carbodiimide:WSC)(223 mg)および4−ジチオカルバミルメチル安息香酸(165 mg)を含む2,2,2-トリフルオロエタノール溶液(6 mL)を0℃で1時間攪拌した後、ゼラチン(PSKゼラチン、ニッピ社製、300 mg)、N−ヒドロキシスクシンイミド(NHS)57 mgおよびジメチルアミノピリジン(DMAP)60 mgを含むTFE溶液(6 mL)に室温で加えた。該溶液を1日攪拌した。該溶液をろ過し、水にて希釈した。該ろ液を3日間透析し(ダイアリシスメンブラン36、和光純薬製)、凍結乾燥した。ジチオカルバミル基の導入量を得られた凍結乾燥体をUV-可視スペクトルにより280 nmの吸光度を測定することにより算出したところ、85%のアミノ基がジチオカルバミル化されたゼラチンを得た。
ここで、4−ジチオカルバミルメチル安息香酸のcLogPは3.6であり、疎水性である。また、ジチオカルバミル基はアルカリにより分解を受け、チオールを産生する官能基である。
WSC(同人化学社製)38.4mg(テレフタル酸の2倍モル量)とテレフタル酸16.6 mgを含むHFIP溶液(1 mL)を4℃で1時間攪拌し、カルボキシル基を活性かした後、酸処理ゼラチン(PSKゼラチン、ニッピ社製)を600 mg、N−ヒドロキシスクシンイミド(NHS)115 mgおよびジメチルアミノピリジン(DMAP)122 mg含むTFE溶液(2 mL)に加えた。該溶液を室温にて3時間静置すると、溶液全体がゲル状に硬化した。
WSC(223 mg)および4−ジチオカルバミルメチル安息香酸(165 mg)を含む2,2,2-トリフルオロエタノール溶液(6 mL)を0℃で1時間攪拌した後、ゼラチン(PSKゼラチン、ニッピ社製、300 mg)、N−ヒドロキシスクシンイミド(NHS)57 mgおよびジメチルアミノピリジン(DMAP)60 mgを含むTFE-HFIP混合溶液(6 mL、TFE/HFIP=5)に室温で加えた。該溶液を1日攪拌した。該溶液をろ過し、水にて希釈した。該ろ液を3日間透析し(ダイアリシスメンブラン36、和光純薬製)、凍結乾燥した。ジチオカルバミル基の導入量を得られた凍結乾燥体をUV-可視スペクトルにより280 nmの吸光度を測定することにより算出したところ、75%のアミノ基がジチオカルバミル化されたゼラチンを得た。
Claims (6)
- 有機フッ素化合物を含む反応溶液中においてポリペプチドを化学修飾することを特徴とする、化学修飾されたポリペプチドの製造方法であって、有機フッ素化合物が、2,2,2−トリフルオロエタノール又は1,1,1,3,3,3-ヘキサフルオロ-2-プロパノールであり、ポリペプチドがコラーゲン又はゼラチンであり、化学修飾が、アミド結合又はエステル結合を介してなる化学修飾である、上記の製造方法。
- ポリペプチドがゼラチンである、請求項1に記載の方法。
- 化学修飾が、分子間の架橋反応、又は分子内の架橋反応である、請求項1又は2に記載の方法。
- 化学修飾が、ポリペプチドへの官能基の導入である、請求項1又は2に記載の方法。
- 縮合剤を用いて化学修飾を行う、請求項1から4の何れかに記載の方法。
- 有機フッ素化合物が2,2,2−トリフルオロエタノールである、請求項1から5の何れかに記載の方法。
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JP2007537314A (ja) * | 2004-05-12 | 2007-12-20 | ゲリタ アクチェンゲゼルシャフト | 架橋したゼラチンを基にした造形体の製造法 |
WO2008072379A1 (ja) * | 2006-12-13 | 2008-06-19 | Fujifilm Corporation | 修飾された生体高分子の製造方法及び生体高分子の架橋方法 |
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US20100323421A1 (en) | 2010-12-23 |
EP2221334A1 (en) | 2010-08-25 |
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US8507659B2 (en) | 2013-08-13 |
JPWO2009069727A1 (ja) | 2011-04-14 |
EP2221334B1 (en) | 2016-12-28 |
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