JP6546232B2 - 抗炎症活性を有するペプチド、及びそれを含む組成物 - Google Patents
抗炎症活性を有するペプチド、及びそれを含む組成物 Download PDFInfo
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
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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)鎖配向に影響を及ぼす残基:gly、pro;及び
(6)芳香族:trp、tyr、phe。
実験例1:PEP 1(配列番号1)の合成
ヒトテロメラーゼから選別された下記配列SEQ ID:1(PEP 1)を有する下記化学構造1を有する16個のアミノ酸から構成されたペプチドを合成した。
NH2−Ala−2−chloro−Trityl Resin
NH2−Arg(Pbf)−2−chloro−Trityl Resin
1)カップリング
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。
2)Fmoc脱保護
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。
3)1及び2の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(Boc)−2−chloro−Trityl Resin)を作った。
4)切断(cleavage):合成が完了したペプチドResinに、切断カクテル(cleavage cocktail)を加え、ペプチドをレジンから分離した。
5)得られた混合物(mixture)に、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る。
6)Prep−HPLCで精製した後、LC/MSで分子量を確認して凍結させ、パウダーに製造した。
細胞株培養
韓国細胞株銀行から分譲されたRaw 264.7macrophage cell(KCBL、40071)は、10% fetal bovine serum(FBS;Gibco Laboratories)と、100unit/mLのstreptomycin及びpenicillin(Gibco Laboratories)が添加されたDulbecco’s modified Eagle’s medium(DMEM;PAA,Austria)培地を使用して、1×106細胞/mlに調節した後、96ウェルプレートに接種し、37゜C、5% CO2の条件で前培養した。
酸化窒素の定量は、Raw 264.7細胞(1×106細胞/ml)を利用して、グリース反応液システム(Griess reagent system;Promega,USA)を使用して測定する方法を使用した。96−ウェルプレートに培養液50μlを入れ、グリース反応液I(ナフチルエチレンジアミド(NED)溶液)及びグリース反応液II(スルファニルアミド溶液)を同量で混合して入れ、10分間の反応後、30分以内に、マイクロプレートリーダー(Molecular Devices,USA)を利用して、光学密度540nmで測定した。酸化窒素(NO)の濃度は、亜硝酸ナトリウムの標準曲線(0〜100μM)を利用して計算した
下記表3に示されているように、LPSは、NOの生成を増加させたが、LPSとペプチドPEP 1とを同時に処理した場合、NO生成量が減少するということを確認することができた。特に、PEP 1を処理した場合には、炎症の誘発時に生成されるNOの生成量が65%減少したと推し量るとき、炎症誘発が抑制されたということが分かった。
PEP 1の炎症性サイトカイン生成抑制効果を調査するために、RAW 264.7cellを、ヒトテロメラーゼ由来PEP 15μg/mL濃度でまず処理した後、LPS 1μg/mL濃度で処理し、24時間さらに培養した。細胞培養液(culture medium)を含む上澄み液サンプルを採集し、ELISAキット(eBioscience,San Diego)を使用して、サイトカインレベルを分析した。
下記表4に示されているように、LPSは、サイトカインIL−6(interleukin−6)の分泌を増加させたが、LPS及びPEP 1を同時に処理した場合、炎症関連サイトカインIL−6の分泌量が減少するということを確認するということができた。特に、PEP 1を処理した場合には、炎症誘発関連サイトカインの分泌量を70%超減少させ、すぐれた抗炎活性を示した。
タンパク質発現の分析は、ウェスタンブロット分析(Western blot analysis)によって行ったが、ヒトテロメラーゼ由来ペプチドが処理された培地で育った細胞をPBSで洗浄し、0.05%トリプシン−EDTAを処理した後、遠心分離を行って細胞を集めた。そのように集められた細胞に、適量のリシスバッファで溶解させた後、細胞内残渣物を分離させ、同量のタンパク質をSDS−ポリアクリルアミドゲル電気泳動で分離した。分離されたタンパク質を、ニトロセルロース膜(nitrocellulose membrane;Schleicherand Schuell,Keene,NH,USA)に転移させた後、特定タンパク質に対する抗体と、それに対する二次抗体との反応を実施した後、ECL(enhanced chemiluminoesence)溶液(Amersham Life Science Corp.,Arlington Heights,IL,USA)を適用させた後、X線フィルムに感光させ、タンパク質の発現程度を分析した。
実験例3−1:細胞株培養
健常者から血液を採血(50ml)した後、Ficoll−PaqueTM PLUS(GE Healthcare Life Sciences,Piscataway,NJ,USA)を使用して、PBMC(peripheral blood mononuclear cell)層を回収した。回収されたPBMCは、ヒト血清(20%)が添加されたRPMI 1640培地(Invitrogen/Life Technologies,Carlsbad,CA,USA)で富化させ、30分ほどヒト血清をコーティングした100−mmポリスチレン細胞培養プレートに移し、2時間37℃、5%CO2インキュベータで培養した。その後、細胞培養プレートの底に付着したモノサイトを、冷たいPBS(Phosphate Buffered Saline)(Gibco/Life Technologies,Carlsbad,CA,USA)で引き離した後、96ウェルプレートに、ウェル当たり1×105セルになるように、RPMI 1640培地(supplemented with penicillin-streptomycin;100mg/ml、human serum;20%)で実験前日に培養した。
PEP 1がTNF−αのタンパク質発現程度に、いかなる影響を及ぼすかということを調べるために、ELISA(enzyme linked immunosorbent assay)実験を行った。PBMCに由来したモノサイトを、96ウェルプレートに、ウェル当たり1×105セルになるように実験前日に培養させた。その後、LPS(lipopolysaccharide;10ng/ml、Sigma)を2時間処理し、PBSで3回洗浄した。OPTI−MEM培地(Invitrogen/Life Technologies,Carlsbad,CA,USA)を入れ、1時間飢餓状態処理(starvation)した後、FITC(Fluorescein Isothiocyanate)、FITC−TAT、PEP 1−FITC及びFITC−PEP 1の4μMで処理し、TNF−αレベル測定前に2時間培養した。培養が終了した後、細胞培養液を集め、ELISA(R&D,Minneapolis,MN,USA)キットマニュアルによってTNF−αを定量した。具体的な定量方法は、次の通りである。
炎症反応(inflammatory response)でのPEP 1の役割を調査するため、ルシフェラーゼ分析(Luciferase assay)を介して、NF−kB発現パターン(expression patterns)を評価した。第一に、12ウェルプレートに、ウェル当たり2.5x105セルになるように、HEK293/nullと、HEK293/TLR 2(Graduate School of Dentistry,Seoul National University)を24時間培養した。プレートをPBSで3回洗浄した後、培地は、OPTI−MEM(Invitrogen/Life Technologies,Carlsbad,CA,USA)に交換して4時間培養した後、3μl lipofectamine(Invitrogen/Life Technologies)、1μl NF−kB ルシフェラーゼ、10ng renilla luciferase(Promega,Madison,WI,USA)混合物を各ウェルに加えた後、4時間さらに培養した。陰性対照群を除外した全てのウェルに、Lipoprotein pam3cys(10ng/ml、Sigma−Aldrich,St.Louis,MO,USA)を加え、PBSで3回洗浄する前に、18時間FITC(4μM)とFITC−PEP 1(4μM)とで処理した。dual-luciferase reporter assayシステム(Promega)によって提供されることにより、それぞれのウェルに、50μl passive溶解緩衝剤(lysis buffer)を加えて細胞を溶解させた後、TD−20/20 luminometer(Turner designs,Sunnyvale,CA,USA)を介して、NF−kB活性化を確認した。Pcmv−renilla luciferase(Promega)のコトランスフェクションで、トレンスフェクション効能を確認し、ルシフェラーゼ値をcalibrateして結果を分析した。
ヒト急性単核球性白血病(Human acute monocytic leukemia)細胞株であるTHP−1細胞(ATSS:American Type Culture Collection,Manassas,VA,USA)を使用して、PEP 1の効能を再確認した。細胞は、密度0.5−0.7x105cells/mLのRPMI 1640において、このときRPMI 1640は、10% FBS、0.05mM 2−メルカプトエタノール、100U/mlペニシリン、100μg/mLストレプトマイシンを含み、37℃の5%CO2で維持された。THP−1細胞は、PMA(phorbol myristate acetate)100ng/mLを24時間37℃で処理し、大食細胞に分化させた。
HMGB1タンパク質は、外部刺激によって、核内に存在するHMGB1タンパク質がアセチル化されて細胞質に移動していて、その後、細胞外部に分泌されることにより、炎症誘発サイトカインの役割を行うと知られている。このように、炎症がある場合、HMGB1タンパク質が細胞外部に分泌されるので、炎症性疾患であるチャーグ・ストラウス症侯群、リューマチ関節炎及びシェーグレン症候群の患者の血清は、正常人よりはるかに多量のHMGB1タンパク質を有する。従って、炎症が誘発されるいかなる刺激が与えられても、細胞核内のHMGB1タンパク質量が多ければ、それは、HMGB1タンパク質が細胞外部に分泌していないということを意味するので、炎症が抑制されていると見られる。
まず、PEP 1を、実施例1に記載されたペプチドの製造方法によって準備した。
妊娠13日目の胎児ラットの頭から大脳皮質を分離した後、次のような培養条件で1週間、bFGF(Basic Fibroblast Growth Factor)で処理し、神経幹細胞を確保した。ベータアミロイドタンパク質が、前記培養された神経幹細胞に及ぼす影響を分析するために、あらかじめオリゴマー化させたベータアミロイドタンパク質を、0μMで、40μM濃度で神経幹細胞を48時間処理した後、CCK−8アッセイ、BrdU及びTUNELアッセイ利用して、細胞毒性評価を実施した。20μMのベータアミロイドタンパク質の処理後、60%ほどに細胞生存率が低下するということを確認し、前述のところと同一の濃度(0μM〜40μM)を、その後の実験に利用した(図47及び図48参照)。
PEP 1が、前記培養された神経幹細胞に及ぼす影響を分析するために、既存に周知の方法によって、あらかじめ0,1,10,50,100,200μMまで多様な濃度で処理した後、MTTアッセイ、BrdU及びTUNELアッセイを利用して、細胞生存率と細胞増殖程度との評価を実施した。PEP 1の0ないし200μMの濃度では、細胞の生存及び増殖を阻害しないということが分かり、神経細胞系で安定しているということが確認された(図49及び図50参照)。
PEP 1がベータアミロイドタンパク質の神経毒性を抑制する効果があるか否かということを確認するために、20μMベータアミロイドタンパク質と、多様な濃度のPEP 1とで48時間処理後、細胞生存率及び死滅程度を、MTTアッセイ、CCK−8アッセイ、LDHアッセイ及びTUNELアッセイを利用して評価し、BrdUアッセイを利用して、神経幹細胞の増殖程度を分析した。
PEP 1処理された群と、処理されていない群とのタンパク質発現量を、2D−電気泳動技法(2−D gel electrophoresis)及び抗体マイクロアレイ(antibody microarray)技法で分析して定量した。前記実施例3の実験例1−1で培養された神経幹細胞から、プロテオームを抽出して200μgを準備し、PEP 1が処理されていない群を比較群として使用して、同一条件で比較分析した。
実験方法
THP−1細胞培養
ヒト急性単核球性白血病(Human acute monocytic leukemia)細胞株であるTHP−1細胞(ATCC:American Type Culture Collection(ATCC),Manassas,VA,USA)を使用して実験を進めた。THP−1を96ウェルプレートに、ウェル当たり1×105セルになるように、RPMI 1640培地で富化させ、24時間培養させた。懸濁液で正常に成長するTHP−1細胞は、付着大食細胞類似表現型(adherent macrophage-lik ephenotype)に分化され、それは、分化培地で24時間行われた(100ng/mLのphorbol 12−myristate 13−actate(PMA;Sigma−Aldrich)を含む完全成長培地条件)。分化の間、THP−1細胞(3x106cells/plate、〜95%コンフルエンシー(増殖尺度))は、10/cmの組織培養プレートにシードされ、分化培地で培養された。
分化後に、大食細胞類似THP−1細胞は、完全成長培地で2回洗浄された。その後、細胞は、10ng/mLのリポ多糖(Sigma−Aldrich)及び/または4μMのPEP−1で4時間37℃で処理された。
トータルRNAは、RNeasyminikit(Qiagen,Valencia,CA,USAから購入)を使用して抽出及び精製され、製造社のプロトコルに従った。cDNAは、逆転写を介して合成され、Reverse Transcription System(Madison,WI,USAで購入)を使用して、製造社のプロトコルに従った。
その後、THP−1細胞から得たcDNAサンプルは、リアルタイム定量PCR(qPCR:real−time quantitative PCR)分析のテンプレートとして使用された。qPCR分析のために、RT2 Profilier PCRアレイキットを、SABiosciences/Qiagen(Valencia,CA,USA)から購入した。分離された信号伝達を分析する4個の異なるPCRアレイキットが実験に使用され、詳細な内容は、次の通りである:ヒト信号変換メカニズムファインダ、ヒト炎症サイトカイン及び受容体、ヒト転写因子、ヒトNF−κB信号メカニズム。PCRは、Bio−Rad(Mercules,CA,USA)のCFX 96リアルタイムPCR機器を使用して、SYBR Green感知システム(Qiagen)を介して行われた。
Claims (8)
- 中枢または末梢神経系関連炎症性疾患の治療または予防のための医薬組成物であって、配列番号1のアミノ酸配列からなるペプチドを有効成分として含む、医薬組成物。
- 前記疾患がアルツハイマー病である、請求項1に記載の組成物。
- 0.1μg/mg〜1mg/mgの前記ペプチドを含む、請求項1又は2に記載の組成物。
- 前記ペプチドが0.1μg/kg〜1.0g/kgの単回投与用量で投与される、請求項1又は2に記載の組成物。
- 前記ペプチドが1μg/kg〜10mg/kgの単回投与用量で投与される、請求項1又は2に記載の組成物。
- 前記ペプチドが0.1μg/kg〜1.0g/kgの1日投与用量で投与される、請求項1又は2に記載の組成物。
- 1日に1〜3回投与される、請求項1又は2に記載の組成物。
- 経口、直腸、経皮、静脈内、筋肉内、腹腔内、骨髄内、硬膜外または皮下手段を通じて投与される、請求項1〜7のいずれか1項に記載の組成物。
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