JP2013509389A - 治療用ペプチド - Google Patents
治療用ペプチド Download PDFInfo
- Publication number
- JP2013509389A JP2013509389A JP2012535924A JP2012535924A JP2013509389A JP 2013509389 A JP2013509389 A JP 2013509389A JP 2012535924 A JP2012535924 A JP 2012535924A JP 2012535924 A JP2012535924 A JP 2012535924A JP 2013509389 A JP2013509389 A JP 2013509389A
- Authority
- JP
- Japan
- Prior art keywords
- amino acid
- peptide
- peptidomimetic
- acid derivative
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- 125000001424 substituent group Chemical group 0.000 claims abstract description 49
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Abstract
【選択図】図2
Description
ここで、XはO、C、NまたはSを表すが、化合物N−メチル−L−フェニルアラニル−L−リシル−L−プロリル−2,2−ビ(フェニルメチル)−β−アラニル−D−アルギニンおよびN−メチル−L−フェニルアラニル−L−リシル−L−プロリル−D−シクロヘキシルアラニル−2,2−ビ(フェニルメチル)−β−アラニル−D−アルギニンを除外する。]
IUPAC系ではなくケミカルアブストラクト型命名法を使用すると、上記の2つの分子は、D−アルギニン、N2−[N−[1−[N2−(N−メチル−L−フェニルアラニル)−L−リシル]−L−プロリル]−2,2−ビ(フェニルメチル)−β−アラニル]およびD−アルギニン、N2−[N−[3−シクロヘキシル−N−[1−[N2−(N−メチル−L−フェニルアラニル)−L−リシル]−L−プロリル]−D−アラニル]−2,2−ビ(フェニルメチル)−β−アラニル]と呼ばれ、これらのCAS番号はそれぞれ145149−42−4および145149−43−5である。
本明細書において記載される分子は、本来細胞溶解性であり、抗菌性剤antimcrobial、例えば、抗菌剤または抗真菌剤、抗菌の好ましい使用として特に有益である。分子の特異性はまた、分子を抗腫瘍剤として適切にする。したがって、さらなる態様において、本発明は、下記式Iの基を組み込んだ、少なくとも+2の正味の陽電荷を有する、治療に使用するためのペプチド、ペプチド模倣体または(修飾)アミノ酸を提供する。
本発明は、下記式Iの基を組み込んだ、少なくとも+2の正味の陽電荷を有する、細胞溶解剤として使用するためのペプチド、ペプチド模倣体または(修飾)アミノ酸をさらに提供する。
α−キモトリプシンに対する安定性
α−キモトリプシンに対する安定性試験を、所望の化合物を水に溶解して1mg/mlにすることにより行った。α−キモトリプシンは、2mMCaCl2を含有する1mMHClに溶解して0.1mg/mlにした。酵素消化は、10mMCaCl2を含有する100mMトリスHCl中で行った。最終酵素濃度は2μg/mlであり、最終ペプチド濃度は100μg/mlであった。合計体積は0.5mlであった。
結果
実施例2
本発明のさらなる分子を製造し、抗菌および抗癌活性の両方を試験した。
材料および方法
細菌株
黄色ブドウ球菌(ATTC25923)
メチシリン耐性黄色ブドウ球菌(ATCC33591)
メチシリン耐性表皮ブドウ球菌(ATCC27626)
大腸菌(ATTC25922)
癌細胞系統
A20またはMethA
使用する毒性試験の細胞
MRC−5およびヒトRBC
様々なアッセイで試験した最高濃度は、
抗菌性アッセイ:200μg/ml
抗癌性アッセイ:500μg/ml
MRC−5アッセイ:500μg/ml
RBCアッセイ:1000μg/ml
ChemDraw Ultra版11.0を、生理化学的特性LogP、tPSAおよびCLogPを算定するために使用した。
分子の合成
樹脂の膨潤:RinkアミドMBHA樹脂(0.64mmol/g装填)を7mlDMFに1時間膨潤させ、DMF7mlで5回洗浄した。
Fmoc−除去:DMF中の20%ピペリジン7mlを反応管に添加し、懸濁液を10分間撹拌し、溶液を除去した。この手順は、1分間撹拌しながら2回反復し、樹脂をDMF7mlで5回洗浄した。
脱保護樹脂へのアミノ酸のカップリング:Fmoc−Lys(Boc)−OHまたはFmoc−Trp(Boc)−OH(4当量)、HOBt水和物(4当量)およびHBTU(3.92当量)を5mlDMFに溶解し、DIPEA(8当量)を添加し、混合物は15分間前もって活性化しておき、樹脂に添加した。1時間撹拌した後、カップリング混合物を除去し、樹脂は7mlのDMFで5回洗浄した。
β−アミノ酸の脱保護樹脂へのカップリング:Fmoc−β−aa−OH(2当量)およびTFFH(1.96当量)をDMF5mlに溶解し、DIPEA(8当量)を添加し、混合物は15分間前もって活性化し、樹脂に添加した。48時間撹拌した後に、カップリング混合物を除去し、樹脂はDMF7mlで5回洗浄した。
β−アミノ酸後のアミノ酸の脱保護樹脂へのカップリング:Fmoc−Trp(Boc)−OH(4当量)およびTFFH(3.92当量)をDMF5mlに溶解し、DIPEA(8当量)を添加し、混合物を15分間前もって活性化させ、樹脂に添加した。24時間撹拌した後、カップリング混合物を除去し、樹脂はDMF7mlで5回洗浄した。最後のカップリングの後、樹脂はDCMで5回洗浄し、終夜風乾した。
樹脂からの開裂およびBoc除去:TFA:TIS:水(95:2.5:2.5)10mlを反応管に添加し、懸濁液は2時間撹拌し、ペプチド溶液を収集した。この手順は、10分間撹拌しながら2度反復した。収集したペプチド溶液を減圧下で蒸発乾固させ、ジエチルエーテルで沈澱させ、ジエチルエーテルで洗浄した。ペプチドはHPLCによって精製し凍結乾燥した。
細胞試験
好適な方法論は実施例1に記載されている。
結果
実施例2に記載された化合物7は、2つの正常細胞系統および9つの癌細胞系統からふるい分けした。
本発明のβ2,2−アミノ酸誘導体を製造し、抗菌活性について試験し、経口投与に対するそれらの適合性を調べた。
合成
β2,2−アミノ酸誘導体(図3)は、図4に示す方式によって合成した。β−アミノを調製する方法の広範囲を覆う総説の間としてAbele,S.ら、Eur.J.Org.Chem.[2000]2000,1−15.を参照のこと。Boc保護β2,2−アミノ酸3a−dを4つの異なるC末端陽イオン基(図4)にカップリングさせた。収率を改善するために、カップリング試薬TFFHの1.5当量は、最終のカップリングステップにおいて使用された。β2,2−アミノ酸も、標準10分の代わりにTFFHで2時間前もって活性化した。カップリング反応の後、質量分光分析を行い、Na2CO3水溶液の添加によって終了させた。しかし、立体障害によって、C末端陽イオン基の結合にカップリング時間は、7日まで延長しなければならなかった。
1a〜dの合成の一般手順
合成は、以前に報告されたCroninら Anal.Biochem.[1982]124,139−149による合成に基づいていた。手短には、ナトリウムメトキシド(20mmol)をメタノールに溶解して0.2Mのおよその濃度を達成し、シアノ酢酸メチル(20mmol)を添加し、反応混合物を室温で5分間撹拌した。所望の臭化ベンジル(20mmol)を添加し、溶液は加熱して15分間還流し、溶液を室温に冷却し、ナトリウムメトキシド(20mmol)の第2の部分を添加した。室温で5分撹拌後、所望の臭化ベンジル(20mmol)の別の部分を添加し、さらに15分還流した。メタノールのおよそ2/3を真空内で除去し、反応混合物を酢酸エチルで希釈し、水で洗浄した。有機相はMgSO4で乾燥し、濾過し、蒸発乾固させた。生成物1a−dは、さらなる精製をすることなく以下の合成に使用した。
2a〜dの合成の一般手順
合成は上記CroninらおよびBodanszkyら“The practice
of peptide synthesis”Springe−Verlag 1994
.によって以前報告された合成に基づいた。手短には、Ra/Ni(通常2mL)を、メタノールで洗浄して水分を除去し、所望のシアノ酢酸メチル誘導体(1a〜d)(3.5mmol)を酢酸(通常1ml)およびメタノールと共に添加し、およそ0.1mの1a〜dの最終濃度を得た。反応物混合物は、搭載した還流凝縮器で1バールのH2で45℃で5日間水素化し、Ra/Niを濾過し、反応混合物は蒸発乾固させた。粗のβ2,2−アミノ酸メチルエステルを1,4−ジオキサンと水の5:1混合物(0.35M)に溶解し、pHをTEAで8に調節し、可能な限り少量の1,4−ジオキサンに溶解したBoc2O(1.5当量)を添加し、溶液は18時間室温で撹拌した。反応混合物は0.1mHClでpH4〜5に酸性化し、酢酸エチルで3回抽出し有機相をMgSO4で乾燥し、濾過し、蒸発乾固させた。粗生成物2a〜dは、さらなる精製をすることなく以下の合成に使用した。
3a〜dの合成の一般手順。
4a〜d、5a〜d、6a〜d、および7a〜dの合成の一般手順
この合成は、ChanおよびWhite、「Fmoc固相ペプチド合成:実際的な手法」Oxford University Press 2000;p346の文献に基づいた。手短には、Boc保護β2,2−アミノ酸(3a〜d)(通常0.2mmol)をDMF(0.02M)に溶解し、DIPEA(3当量)はTFFH(1当量)と共に添加した。β2,2−アミノ酸を2時間活性化させ、所望のアミンを添加した(2当量)。反応物は続いてMSを行い、最大7日間反応させ、酢酸エチルで希釈し、塩水で洗浄した。有機相はMgSO4で乾燥し、濾過し、蒸発乾固させた。Boc保護β2,2−アミノ酸誘導体をDCMにそれらを溶解することにより脱保護し、等しい体積のTFA:TIS:水(95:2.5:2.5)を添加し2時間室温で撹拌し、蒸発乾固させた。粗生成物を分取RPHPLCによって精製し、凍結乾燥した。化合物の純度は、分析HPLCによって210nmから310nmにわたるPDA検出器で点検した。すべての化合物は95%を超える純度を有していた。
抗菌活性
各化合物は、200、100、50、35、15、10、5、2.5、1、0.5mg/mlで二重反復試験した。試験した化合物はすべて、二−トリフルオロ酢酸塩であった。
溶血作用
ヘパリン処理したヒト血液の血漿分画を、遠心分離、および前もって37℃に暖めたリン酸緩衝生理食塩水(PBS)での3つの追加の洗浄ステップによって最初に除去した。続いて、ヒトRBCを10%ヘマトクリットに希釈し、β2,2−アミノ酸誘導体をPBSに溶解して1〜1000μg/mLの範囲の濃度を提供した。希釈したRBCを化合物の溶液に添加し、1%v/vの最終赤血球濃度にした。0.1%v/vの最終濃度のPBSおよびトリトンX−100は、負および正の対照として包含されていた。揺動しながら37℃で1時間のインキュベーションの後、試料を5分間4000rpmで遠心分離機にかけた。ヘモグロビンの放出は、405nmで上澄みの吸光度を測定することにより求めた。溶血作用は、β2,2−アミノ酸誘導体で処理した試料と、界面活性剤で処理した試料の比率として、下記式によって算定した。
Maestroソフトウェアv9.1に包含されている
QikProp適用の使用によってリピンスキーのルール
オブファイブに関するβ2,2−アミノ酸誘導体の薬らしさの評価を、ヒトのパーセント経口吸収の評価と一緒に見積もった。ルールは、経口活性薬物が以下の4つの基準の2つ以上を破るべきでないと述べる。1)オクタノール−水分配係数logPが5未満であるべきである。2)分子量(Mw)は500ダルトンを上回るべきでない。3)最大5個の水素結合供与体(HBD)基は許容される。および、4)10以下の水素結合受容体(HBA)基があること。結果は、下記表10に提示される。
ソフトウェアによるヒトにおいてパーセント経口吸収の計算は、すべてのβ2,2−アミノ酸誘導体が、89%から62%の範囲に算定された経口吸収を有することによりかなりよく吸収されるであろうという結論を下した。最も高いパーセント経口吸収は、β2,2−アミノ酸誘導体5a、5b、5c、6bおよび6cに算定した86%〜89%の経口吸収の範囲にすべてあった。
浸透性
理論計算に励まされて、β2,2−アミノ酸誘導体の浸透性を、最近確立されたリン脂質小胞系のバリアモデルを使用してさらに調べた(Flatenら Eur.J.Pharm.Sci.[2006]27,80−90)。MRSAおよび大腸菌に対する同様の効力を示す、4種のβ2,2−アミノ酸誘導体(4c、5c、6cおよび7c)を調べた。モデルの吸収の分類に基づいて、4種の化合物すべてがヒトに中程度に吸収されることと等価な浸透性を示した。実験的な浸透性値のために、化合物5cは、最も高い浸透性を示し、化合物6c、4c、および7cが続いた。
Claims (19)
- 少なくとも+2の正味の陽電荷を有し、二置換β−アミノ酸を組み込んだ、ペプチド、ペプチド模倣体またはアミノ酸誘導体であって、β−アミノ酸中の各置換基が、同一または異なっていてよく、少なくとも7個の非水素原子を含み、親油性であり、少なくとも1個の環式基を有し、一方の置換基内の1個または複数の環式基は、他方の置換基内の1個または複数の環式基に連結または縮合されていてもよく、また、環式基がこのように縮合されている場合、2個の置換基の非水素原子の総計数が少なくとも12である、細胞溶解治療剤としての使用のための、ペプチド、ペプチド模倣体またはアミノ酸誘導体。
- 2個の置換基が同一である、請求項1に記載の使用。
- β−アミノ酸がβ2,2またはβ3,3−二置換アミノ酸である、請求項1または2に記載の使用。
- 各親油性置換基が場合によって置換されたフェニルまたはシクロヘキシル基を含む、請求項1から3に記載の使用。
- 前記フェニルまたはシクロヘキシル基がβ−アミノ酸のαまたはβ炭素原子から1から4個の連結原子によって分離されている、請求項4に記載の使用。
- 各親油性置換基が8から12の非水素原子を含む、請求項1から5に記載の使用。
- ペプチド、ペプチド模倣体またはアミノ酸誘導体が、長さで1から12のアミノ酸、または等価なサブユニットである、請求項1から6に記載の使用。
- ペプチド、ペプチド模倣体またはアミノ酸誘導体のC末端がアミド化され、場合によって置換されている、請求項1から7に記載の使用。
- ペプチドまたはペプチド模倣体が、陽イオン性アミノ酸、好ましくはアルギニンまたはリシンを組み込んでいる、請求項1から8に記載の使用。
- 抗生物質としての使用のための、請求項1から9に定義されるペプチド、ペプチド模倣体またはアミノ酸誘導体。
- 抗腫瘍剤としての使用のための、請求項1から9のいずれか一項に定義されるペプチド、ペプチド模倣体またはアミノ酸誘導体。
- 細胞溶解剤としての使用のための、請求項1から9のいずれか一項に定義されるペプチド、ペプチド模倣体またはアミノ酸誘導体の生体外の使用。
- 請求項1から9のいずれか一項に定義されるペプチド、ペプチド模倣体またはアミノ酸誘導体の対象への投与を含む、菌感染を治療する方法。
- 腫瘍細胞を処置する、あるいは腫瘍の成長、定着の伝播、または転移を阻止するもしくは減少させる方法であって、請求項1から9のいずれか一項に定義されるペプチド、ペプチド模倣体またはアミノ酸誘導体の対象への投与を含む、方法。
- 下記式Iの基を組み込んだ、少なくとも+2の正味の陽電荷を有するペプチド、ペプチド模倣体またはアミノ酸誘導体。
- 請求項15に記載の分子および希釈剤、担体または賦形剤を含む配合物。
- 治療での使用のための、請求項15に記載のペプチド、ペプチド模倣体またはアミノ酸誘導体。
- (a)請求項1から9のいずれか一項に定義される、または請求項15に記載の、ペプチド、ペプチド模倣体またはアミノ酸誘導体、および(b)抗菌性感染症の治療における別々の、同時のまたは連続する使用のための組み合わせた調製としてのさらなる抗生物質を含む生成物。
- (a)請求項1から9のいずれか一項に定義される、または請求項15に記載の、ペプチド、ペプチド模倣体またはアミノ酸誘導体、および(b)腫瘍細胞の処置における別々の、同時のまたは連続する使用のための組み合わせた調製としてのさらなる抗腫瘍剤を含む生成物。
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Application Number | Priority Date | Filing Date | Title |
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GBGB0919194.1A GB0919194D0 (en) | 2009-11-02 | 2009-11-02 | Compounds |
PCT/GB2010/002024 WO2011051692A1 (en) | 2009-11-02 | 2010-11-02 | Therapeutic peptides |
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WO2017179647A1 (ja) * | 2016-04-14 | 2017-10-19 | Taoヘルスライフファーマ株式会社 | アミロスフェロイド(aspd)結合阻害ペプチド、並びに評価及びスクリーニング方法 |
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HUE054006T2 (hu) | 2011-12-28 | 2021-08-30 | Chugai Pharmaceutical Co Ltd | Eljárás peptid vegyület ciklizálására |
HUE059925T2 (hu) | 2015-03-13 | 2023-01-28 | Chugai Pharmaceutical Co Ltd | Módosított aminoacil-tRNS-szintetáz és alkalmazása |
GB201601868D0 (en) | 2016-02-02 | 2016-03-16 | Lytix Biopharma As | Methods |
GB201705255D0 (en) * | 2017-03-31 | 2017-05-17 | Univ I Tromsø - Norges Arktiske Univ | Bioactive cyclic compounds |
WO2018188761A1 (en) | 2017-04-13 | 2018-10-18 | Lytix Biopharma As | Method of reducing population size of tregs and/or mdscs |
US11542299B2 (en) | 2017-06-09 | 2023-01-03 | Chugai Seiyaku Kabushiki Kaisha | Method for synthesizing peptide containing N-substituted amino acid |
EP3725796A4 (en) | 2017-12-15 | 2021-09-15 | Chugai Seiyaku Kabushiki Kaisha | METHOD FOR MANUFACTURING PEPTIDE AND METHOD FOR PROCESSING BASES |
JPWO2020111238A1 (ja) | 2018-11-30 | 2021-10-21 | 中外製薬株式会社 | ペプチド化合物、またはアミド化合物の脱保護法および固相反応における脱樹脂方法、並びにペプチド化合物の製造方法 |
US12071396B2 (en) | 2019-03-15 | 2024-08-27 | Chugai Seiyaku Kabushiki Kaisha | Method for preparing aromatic amino acid derivative |
CN110294793B (zh) * | 2019-06-24 | 2023-10-27 | 合肥科生景肽生物科技有限公司 | Sumo荧光探针及其制备方法 |
CN114790151B (zh) * | 2022-02-14 | 2023-03-31 | 湖南省湘中制药有限公司 | 一种2-氰基-2-丙戊酸甲酯的复合催化制备方法 |
WO2024133588A1 (en) | 2022-12-20 | 2024-06-27 | Lytix Biopharma As | Compositions comprising an oncolytic peptide and chitosan |
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WO2009081152A2 (en) * | 2007-12-20 | 2009-07-02 | Lytix Biopharma As | Antimicrobial compounds |
EP2105433A1 (en) * | 2008-03-18 | 2009-09-30 | Technische Universität Dresden | Modular scaffold for the design of specific molecules for the use as peptidomimetics and inhibitors of protein interaction |
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Also Published As
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AU2010311186A1 (en) | 2012-05-31 |
AU2010311186B2 (en) | 2015-09-24 |
PL2496596T3 (pl) | 2017-08-31 |
RU2676713C2 (ru) | 2019-01-10 |
RU2012121264A (ru) | 2013-12-10 |
RU2015111706A3 (ja) | 2018-10-29 |
DK2496596T3 (en) | 2017-04-03 |
CN102762586B (zh) | 2016-10-05 |
US8809280B2 (en) | 2014-08-19 |
BR112012010333A2 (pt) | 2016-03-29 |
CA2777749C (en) | 2019-08-06 |
CN102762586A (zh) | 2012-10-31 |
NZ599791A (en) | 2014-10-31 |
JP5810090B2 (ja) | 2015-11-11 |
KR20120104986A (ko) | 2012-09-24 |
CA2777749A1 (en) | 2011-05-05 |
WO2011051692A1 (en) | 2011-05-05 |
KR101730680B1 (ko) | 2017-04-26 |
RU2548905C2 (ru) | 2015-04-20 |
EP2496596A1 (en) | 2012-09-12 |
GB0919194D0 (en) | 2009-12-16 |
US20130035296A1 (en) | 2013-02-07 |
EP2496596B1 (en) | 2017-01-11 |
RU2015111706A (ru) | 2015-11-10 |
ES2621188T3 (es) | 2017-07-03 |
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