JP2018525326A - 新規なtlr4拮抗剤 - Google Patents
新規なtlr4拮抗剤 Download PDFInfo
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- JP2018525326A JP2018525326A JP2017562335A JP2017562335A JP2018525326A JP 2018525326 A JP2018525326 A JP 2018525326A JP 2017562335 A JP2017562335 A JP 2017562335A JP 2017562335 A JP2017562335 A JP 2017562335A JP 2018525326 A JP2018525326 A JP 2018525326A
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Abstract
【解決手段】 本発明によるペプチドは、リポ多糖(LPS)により誘導されるTLR4シグナル伝逹経路を抑制することで、インターロイキン-6(IL-6)、NO及びROSの分泌とNFκB及びMAPKsの活性化を抑制する効果に優れていることから、TLR4シグナル伝逹経路により発生する自己免疫疾患及び炎症性疾患の予防又は治療用組成物として有用に活用することができる。
【選択図】図2
Description
TLR4/MD2複合体に特異的に結合するペプチドを選別するために、15マー(15-mer)ペプチドはfUSE55、12マー(12-mer)ペプチドはpHEN2ファージディスプレイライブラリー(phage display library)を構築し、ファージディスプレイ法(phage display method)を行った。
まず、15マー(15-mer)ペプチドライブラリーを作製するために、順方向(フォワード)プライマー5'-TTG ATC GCA AGG ATC GGC TAG C-3'、逆方向(リバス)プライマー5'-AA GGC CTT GGT ACC GCT GCC ACC (MNN)15 GCT AGC CGA TCC TTG CGA TCA A-3'及びPfuDNA重合酵素(SolGent、Daejeon、Korea)を用いて、90℃で30秒間変性し、55℃で30秒間アニールし、72℃で60秒間伸長する過程を、25回繰り返してDNAを増幅させた。増幅したDNA 鎖をNheI/KpnIで切断した後、T4DNAリガーゼ(New England Biolabs、Inc.、Ipswich、MA、USA)を使用して、fUSE55ベクター中に連結させた。3つのDNAライブラリーを、エレクトロコンピテント大膓菌細胞(electrocompetent E.coli cells)であるDH10B菌株内へと移して、結果として6.6 X 107個のクローンを作成した後、大膓菌菌株TG-1で増幅させ繁殖させた。
変形されたグリフィン-1ライブラリー(Griffin-1 library)(Griffin H.、 MRC、Cambridge、UK、unpublished data)でバイオパニング(Biopanning)を行った。より具体的に、コートされたバッファーで再懸濁された(resuspended)組換えヒトTLR4/MD2複合体(R&D Systems、Inc.、Minneapolis、MN、USA)を5μg/ml、ヌンクマキシソープ96ウェルプレート(Nunc Maxisorp 96-well plate)(Thermo Fisher Scientific Inc.、Waltham、MA、USA)でコートした後、一晩の間冷蔵させた。それから、常温で2時間の間、PBSで1%のBSAによりブロッキングした後、最終濃度0.05%のTween 20を含むPBS(PBST)で、BSAの濃度が1%になるように、常温で2時間の間、前記冷蔵したウェルらをファージライブラリーに露出させた。ライブラリーに結合されたファージらは、溶出緩衝液(100mM HCl)100μlで溶かして分離し、PBSTで洗浄(washing)した後、pH11を示す1M Tris HClの1/8体積(嵩)で中和させた。15マー(15-mer)ライブラリー用のファージ力価(titer)は、200μg/mlのテトラサイクリン(Tet、tetracycline)と10μg/mlのアンピシリン(Amp、ampicillin)を含むLB(Luria-Bertani)寒天プレート上の大膓菌TG1で、12マー(12-mer)ライブラリー用は、大膓菌を前記寒天プレート上のXL-1 BlueでCFUにより計算した。この後、ファージを大膓菌TG1、Xl1 Blueで増幅させ、PEG(polyethylene0glycol)/NaCl沈殿を通じて、続くパニングラウンドの間精製した。全5ラウンドの各ラウンドで、インプット/アウトプットの割合(入出力比)は、濃縮効率を測定して計算し、その結果を図1に示した。
前記実施例1-2において感染された細胞の分離された独立型クローンを、15マーライブラリーのLB/Tetと12マーライブラリーのLB/Amp寒天プレートで、U-バトム(bottom)96ウェルプレートに集めた。それから、5回のバイオパニングのラウンド後、37℃で一晩の間育て、これをLB/TetやLB/Amp寒天プレートに置いた後、上層液のファージ製剤を得るために、3000gの条件で30分間遠心分離させた。ファージ結合親和度を測定するために、PBSに2%のBSAが含まれたバインディングバッファー(binding buffer)と同じ体積(嵩)で混じっている前記上層液を、1.25μg/mlのTLR4/MD2-陽性96ウェルプレートとTLR4/MD2-陰性96ウェルプレートに添加した。前記ウェルらを2時間の間、ブロッキングバッファー(2%のBSAが含まれたPBST)にブロッキングした後、PBSで洗浄した。常温で1時間の間結合反応をさせた後、結合しないファージはPBSTで洗浄して除去し、結合したファージらは、HRP(horseradish peroxidase)にコンジュゲーションされた(conjugated)抗M13抗体100μlで培養した後、結合しない余分のファージらを、PBSTで洗浄して除去することで、結合したファージらを検出した。この後、テトラメチルベンジディン100μl(Thermo Fisher Scientific Inc.)を各ウェルに添加した後、前記混合物を色変化が現われるまで常温に置いた後、反応を止めるために、1N H3PO4を100μl添加した。ELISA(BioTek Instruments、Inc.、Winooski、VT、USA)を用いて、450nmで吸光度を測定することで、高い結合親和度を呈したファージらを選択し、選択されたファージらを下記の実験に使用した。
前記実施例1-3において選択されたファージからファージDNAを分離するために、ミニプレップキット(Miniprerp Kit)(GeneAll Biotechnology、Seoul、Korea)を使用したし、15マーDNAは5'-TGA ATT TCC TGT ATG AGG-3'の塩基配列を有するプリマーを、12マーDNAは5'-TTG TGA GCG GAT AAC AAT TTG-3'の塩基配列を有するプリマーを用いて、マクロジェン(Macrogen、Inc.、Seoul、Korea)でDNAシーケンシング(DNA sequencing)をした。前記シーケンシングを通じて確認したDNA塩基配列をアミノ酸配列へと翻訳し、バイオエディットソフトウェア(Bioedit software)を使用して変異を測定した後、整列した。それから、TLR4/MD2に高い結合親和度を呈する表1のアミノ酸配列を有するペプチド(TAPs; TLR4 agonistic peptidesであって、TAP1、TAP2及びTAP3を総称しており、以下で‘TAPs’という)を、95%以上の純度を有するように、ペップトロン(PEPTRON)(Daejeon、Korea)で合成し、最終濃度が10mg/mlになるように、TAP1は水に、TAP2とTAP3はジメチルスルホキシド(Dimethyl sulfoxide)に溶かした後、-20℃で適当にアリコート(aliquote)して保管した。
HEK-BlueTMhTLR4細胞(InvivoGen、San Diego、CA、USA)を、10%のウシ胎児血清(FBS; fetal bovine serum)(Thermo Fisher Scientific Inc.)、50IU/mlのペニシリン、50μg/mlのストレプトマイシン(Thermo Fisher Scientific Inc.)、100mg/mlのノルモシン(normocin)(InvivoGen)及び抗生剤のHEK-Blue混合物(500ml当たり2ml)(InvivoGen)が添加されたDMEM(Dulbecco's modified Eagle's medium)(Thermo Fisher Scientific Inc.)培地に入れて、5%のCO2、37℃の湿った条件の培養システム(Thermo Fisher Scientific Inc.)で培養した。マウス大食細胞であるRAW264.7細胞(ATCC、Manassas、VA、USA)は、10%のFBS、100IU/mlのペニシリン及び100μg/mlのストレプトマイシンが添加された低グルコースDMEM(Low-Glucose DMEM)(Thermo Fisher Scientific Inc.)に入れて、培養システムで培養した。LPSはSigma-Aldrich Co.(St. Louis、MO、USA)より、PAM3CSK4はInvivogGenより購入した。
TAPs(TAP1、TAP2、TAP3)のTLR4/MD2結合親和度を確認するために、前記実施例3において培養したHEK-BlueTMhTLR4細胞で、NFκBの活性を測定した。NFκBとAP-1(activator protein 1)のDNAが結合する部位を含むIL-12 p40 最小プロモーター(Minimal Promoter)(IL-12 p40は、TLR4の刺激後、NFκBとAP-1の活性化により生成される。)の調節部分の下に、誘導性SEAP(secreted embryonic alkaline phosphatase) レポーター遺伝子を位置させた。その後、TAPsの濃度を10、50、100 μg/mlのように多様にして、HEK-BlueTMhTLR4細胞に処理した後、SEAP活性の平均値を計算してTLR4の活性を測定し、その結果を図2に示した。
前記実施例 2において製造したTAPsを、前記実施例3において培養したマウス大食細胞であるRAW264.7細胞に処理したとき、IL-6(interleukin-6)とNO(Nitric Oxide)の分泌及び細胞質と核内のROS(reactive oxygen species)の発生が抑制されるか否かを確認するために、下記のような実験を行った。
前記実施例2において製造したTAPsを処理した前記実施例3におけるRAW264.7細胞の培養上層液のIL-6、NOの数値を、マウスIL-6 ELISAキットReady-SET-Go!(eBioscience San Diego、CA、USA)と、NO検出キット(iNtRON Biotechnology、Gyeonggi、Korea)を使用して測定した。マイクロプレートリーダー(Microplate Reader)分光光度計(Molecular Devices In.)を使用して、IL-6は450nm、NOは540nmで吸光度を測定し、その結果をソフトマックスのプロ 5.3ソフトウェア(Molecular Devices Inc.)を使用して分析して、図3及び図4に示した。
ウェスタンブロッティング(Western Blotting)を行うために、全タンパク質抽出溶液(M-PER、Thermo Fisher Scientific Inc.)を、プロテアーゼ及びホスファターゼ抑制混合物と混ぜて、前記実施例3におけるRAW264.7細胞ペレット(pellet)に添加した。前記ペレットを10分間冷凍させた後、10分間16000Xgで前記溶解物を遠心分離した。それから、NE-PER核及び細胞質抽出試薬(Thermo Fisher Scientific Inc.)を使用して、細胞質と核のタンパク質をそれぞれ抽出し、BCAキット(Sigma-Alderich Co. LLC)を使用して、前記タンパク質の濃度を測定した。この後、同じ量のタンパク質をSDS-ポリアクリルアマイドゲルに展開し、Hybond-ECL ニトロセルロース膜(Amersham Pharmacia Biotech、Inc.、Piscataway、NJ、USA)へと移した。前記膜を1時間の間、脱イオン水で0.05%の脱脂粉乳によりブロッキングした後、1次抗体により4℃の温度で、一晩の間軽くシェイキング(shaking)して免疫ブロッティング(Immunoblotting;イムノブロット法)した(前記1次抗体は、iNOS(BD Biosciences、San Jose、CA、USA)及びβ-アクチン(Santa Cruz Biotechnology、Inc.、Dallas、TX、USA)に対する抗体である。)。それから、PBSTで徹底的にシェイキングした後、前記膜を抗マウス/ウサギHRP-コンジュゲーションされた(conjugated)2次抗体(Thermo Fisher Scientific Inc.)と共に2時間の間培養し、SuperSignal West Pico ECL溶液(Thermo Fisher Scientific Inc.)でタンパク質を検出し、Fuji LAS-3000システム(Fujifilm、Tokyo、Japan)で前記タンパク質を視覚化したし、その結果を図5に示した。
また、前記実施例2において製造したTAPsが細胞質でNO及びROS(reactive oxygen species)の発生に及ぶ影響を確認するために、前記実施例3において培養したマウス大食細胞であるRAW264.7細胞にTAPsを処理し、それぞれDAF-FM(Invitrogen Corp.、CA、USA)、DCF-DA(Invitrogen Corp.)及びMitoSOX(Invitrogen Corp.)で染色した後、1時間の間培養した。その後、5分当たりに200Xgで遠心分離して収集し、褐色チューブへと移して、4℃の温度でPBSに保管した。前記DAF-FM染色でNOを、DCF-DA 染色で細胞質のROSを、MitoSOX染色でミトコンドリアのROSをそれぞれ定量化(quantification)した。 ディーバソフトウェアとしてFACSAria IIIを使用し、DAF-FM、DCF-DA及びMitoSOX蛍光物質の強度を測定して前記定量化をしたし、WinMDIソフトウェアを使用してイメージを得ており、その結果を図6乃至図8に示した。
前記実施例2において製造したTAPsがNFκB及びMAPKsの活性に及ぶ影響を確認するために、下記の実験を行った。
前記実施例2において製造したTAPsがNFκB及びMAPKsの活性に及ぶ影響を確認するために、ウェスタンブロッティングを前記実験例2-2と同様な方法で行った。このときに使用した1次抗体は、HDAC1(Merck Millipore、Billerica、MA、USA)、NFκB (p65)、IκBα、p-ERK、ERK、p-JNK、JNK、p-p38、p38、ATF3及びβ-アクチン(Santa Cruz Biotechnology、Inc.、Dallas、TX、USA)に対する抗体であり、2次抗体は、抗マウス/ウサギHRP-コンジュゲーションされた(conjugated)2次抗体(Thermo Fisher Scientific Inc.)である。ウェスタンブロッティングを行って得た結果を、図9及び図10に示した。
前記実施例3において培養したHEK-BlueTMhTLR4細胞を、104/wellの96ウェルプレートにシーディング(seeding)した後、2日間インキュベーターで育てた。上層液を交換した後、前記インキュベーター中の細胞にそれぞれTAPsを処理し、1時間後に20μg/mlのLPSをそれぞれ処理した。その後、前記HEK-BlueTMhTLR4細胞を、10分間3.7%のフォルムアルデヒドで固定し、15分間0.2%のトリトンX-100に浸漬した後、1時間の間5.0%のFBSでブロッキングした。前記ブロッキングされた細胞らを、1時間の間1次抗体と共に培養した後、1時間の間AlexaFluor546-コンジュゲーションされた(conjugated)2次抗体(Invitrogen Corp.)と共に培養した。この後、5μMのHoechst33258(Sigma-Aldrich Co.)を用いて、常温で30分間染色をし、共焦点顕微鏡(LSM-700、Carl Zeiss MicroImaging GmbH、Jena、Germany)を使用して、前記蛍光染色された細胞の数を数えたし、Zen2009ソフトウェア(Carl Zeiss MicroImaging GmbH.)を使用して、イメージを分析した後、その結果を図11に示した。
本発明におけるペプチドは、TLR4シグナル伝逹経路を抑制することで、インターロイキン-6(IL-6)、NO及びROSの分泌を抑制する効果と、NFκB及びMAPKsの活性化を抑制する効果に優れていることから、TLR4の拮抗剤として作用することができ、TLR4に関連する自己免疫疾患及び炎症性疾患の予防又は治療用組成物として有用に利用され得る。
Claims (11)
- 配列番号1〜3からなる群より選択された1種以上のアミノ酸配列で表示されるペプチド。
- 前記ペプチドは、TLR4(Toll-like receptor 4)シグナル伝逹経路抑制用であることを特徴とする、請求項1に記載のペプチド。
- 前記TLR4シグナル伝逹経路は、LPS(lipopolysaccharide)により誘導されることを特徴とする、請求項2に記載のペプチド。
- 前記ペプチドは、インターロイキン-6(IL-6; interleukin-6)、NO又はROS(reactive oxygen species)を抑制することを特徴とする、請求項1に記載のペプチド。
- 前記ペプチドは、NFκB又はMAPKsの活性を抑制することを特徴とする、請求項1に記載のペプチド。
- 前記ペプチドは、TLR4/MD2複合体に結合することを特徴とする、請求項1に記載のペプチド。
- 配列番号1〜3からなる群より選択された1種以上のアミノ酸配列で表示されるペプチドを含む、TLR4(Toll-like receptor 4)拮抗剤。
- 配列番号1〜3からなる群より選択された1種以上のアミノ酸配列で表示されるペプチドを有効成分として含む、自己免疫疾患の予防又は治療用組成物。
- 前記自己免疫疾患は、インスリン依存性糖尿病、多発性硬化症、実験的自己免疫性脳脊髓炎、リウマチ性関節炎、実験的自己免疫関節炎、重症筋無力症、甲状腺炎、実験的形態のブドウ膜炎、橋本甲状腺炎、原発性粘液水腫、甲状腺中毒症、悪性貧血、自己免疫性萎縮性胃炎(autoimmune metaplastic atrophic gastritis)、アジソン病、早期閉経(早発閉経)、男性不妊症、小児(子供)糖尿病、グッドパスチャー症候群、尋常性天疱瘡(Pemphigus vulgaris)、類天疱瘡(bullous pemphigoid)、交感性眼炎、水晶体原性ブドウ膜炎(lens-induced uveitis)、自己免疫性溶血性貧血、特発性白血球減少、原発性胆管硬化症(primary biliary sclerosis)、慢性活動性肝炎Hbs-ve、潜在性肝硬変症、潰瘍性大腸炎、ショーグレン症侯群、強皮症、ヴェグナー肉芽腫症(Wegener’s granulomatosis)、多発筋炎/皮膚筋炎、円板状LE(エリテマトーデス)及び全身性紅斑性狼瘡(systemic lupus erythematosus)からなる群より選択された1種以上のものであることを特徴とする、請求項8に記載の自己免疫疾患の予防又は治療用組成物。
- 配列番号1〜3からなる群より選択された1種以上のアミノ酸配列で表示されるペプチドを有効成分として含む、炎症性疾患の予防又は治療用組成物。
- 前記炎症性疾患は、喘息、湿疹、乾癬、アレルギー、リウマチ関節炎、乾癬性関節炎(psoriatic arthritis)、アトピー性皮膚炎、にきび、アトピー性鼻炎、肺炎症、アレルギー性皮膚炎、慢性副鼻腔炎、接触性皮膚炎(contact dermatitis)、脂漏性皮膚炎(seborrheic dermatitis)、胃炎、痛風、痛風性関節炎、潰瘍、慢性気管支炎、クローン病、潰瘍性大腸炎、強直性脊椎炎(ankylosing spondylitis)、敗血症、血管炎(脈管炎)、滑液包炎、狼瘡(lupus)、リウマチ性多発筋痛症、側頭動脈炎、多発性硬化症、固形癌、アルツハイマー病、動脈硬化症、肥満及びウイルス感染からなる群より選択された1種以上のものであることを特徴とする、請求項10に記載の炎症性疾患の予防又は治療用組成物。
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KR102588548B1 (ko) * | 2019-07-16 | 2023-10-16 | 주식회사 젠센 | 자가면역질환 및 염증성질환 펩타이드 치료제 |
KR102353335B1 (ko) * | 2019-10-07 | 2022-01-20 | 제주대학교 산학협력단 | 무궁화 에탄올 추출물의 분획물을 포함하는 tlr4-md2 저해제 조성물 |
CU24626B1 (es) * | 2019-12-26 | 2022-11-07 | Centro Nac De Biopreparados | Composición farmacéutica a base de proteínas con actividad neuroprotectora, inmunomoduladora, antiinflamatoria y antimicrobiana |
KR20230147988A (ko) * | 2022-04-15 | 2023-10-24 | 아주대학교산학협력단 | Rage 길항제 및 age 소거제를 포함하는 당뇨성 뇌졸중 예방 또는 치료용 약학적 조성물 |
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ES2791954T3 (es) | 2020-11-06 |
EP3305803A4 (en) | 2019-01-09 |
CN107922460B (zh) | 2021-08-20 |
EP3305803A1 (en) | 2018-04-11 |
US10435443B2 (en) | 2019-10-08 |
KR101745520B1 (ko) | 2017-06-12 |
KR20160140031A (ko) | 2016-12-07 |
JP6576471B2 (ja) | 2019-09-18 |
EP3305803B1 (en) | 2020-03-11 |
WO2016195159A1 (ko) | 2016-12-08 |
CN107922460A (zh) | 2018-04-17 |
US20180148487A1 (en) | 2018-05-31 |
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