JP2017515816A - 抗炎症、骨形成及び発毛促進活性を有するペプチド及びその用途 - Google Patents
抗炎症、骨形成及び発毛促進活性を有するペプチド及びその用途 Download PDFInfo
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Abstract
Description
(i)本発明は、配列表の配列番号1、配列表の配列番号2及び配列表の配列番号3のアミノ酸配列で構成された群から選択される1種のアミノ酸配列からなる抗炎症及び骨分化促進活性を有するペプチドを提供する。
(ii)本発明は、配列表の配列番号1及び配列表の配列番号3のアミノ酸配列で構成された群から選択される1種のアミノ酸配列からなる発毛促進活性を有するペプチドを提供する。
(iii)本発明の配列表の配列番号1、配列表の配列番号2または配列表の配列番号3のアミノ酸配列からなるペプチドは、炎症性サイトカインの発現を抑制し、炎症細胞の増殖を抑制することによって、結果的に、抗炎症活性を示し、骨形成に関与するPI3K、Smad1、Smad5、及びSmad8のリン酸化を増加させ、ALP、OPG及びBSPの発現を増加させることによって、結果的に、骨分化を促進させる。
(iv)本発明の配列表の配列番号1または配列表の配列番号3のアミノ酸配列からなるペプチドは、毛嚢細胞及び臍帯静脈内皮細胞の増殖を促進させ、ERKのリン酸化を増加させ、毛髪成長に関与するタンパク質であるPI3K、β−カテニン、IGF−1、KGF、Wnt3aの発現を増加させ、脱毛遺伝子であるDKK−1の発現を減少させることによって、結果的に、脱毛予防及び発毛促進効能を示す。
合成例1:ペプチドの合成
クロロトリチルクロライドレジン(Chloro trityl chloride resin;CTL resin、Nova biochem Cat No.01−64−0021)700mgを反応容器に入れ、メチレンクロライド(MC)10mlを加えて3分間撹拌した。溶液を除去し、ジメチルホルムアミド(DMF)10mlを入れて3分間撹拌した後、再び溶媒を除去した。反応器に10mlのジクロロメタン(DCM)溶液を入れ、Fmoc−Cys−OH(Bachem,Swiss)200mmole及びジイソプロピルエチルアミン(DIEA)400mmoleを入れた後、撹拌してよく溶かし、1時間撹拌しながら反応させた。反応後、洗浄し、メタノールとDIEA(2:1)とをDCMに溶かして10分間反応させ、過量のDCM/DMF(1:1)で洗浄した。溶液を除去し、DMFを10ml入れて3分間撹拌した後、再び溶媒を除去した。脱保護溶液(20%のピペリジン(Piperidine)/DMF)10mlを反応容器に入れ、10分間常温で撹拌した後、溶液を除去した。同量の脱保護溶液を入れ、再び10分間反応を保持した後、溶液を除去し、それぞれ3分ずつDMFで2回、MCで1回、DMFで1回洗浄して、Cys−CTLレジンを製造した。新たな反応器に10mlのDMF溶液を入れ、Fmoc− Pro(Bachem,Swiss)200mmole、HoBt 200mmole及びBop 200mmoleを入れた後、撹拌してよく溶かした。反応器に400mmoleのDIEA(N,N−Diisopropylethylamine)を分画で2回に亙って入れた後、あらゆる固体が溶けるまで少なくとも5分間撹拌した。溶かしたアミノ酸混合溶液を脱保護されたレジンがある反応容器に入れ、1時間常温で撹拌しながら反応させた。反応液を除去し、DMF溶液で3回5分ずつ撹拌した後、除去した。反応レジンを少量取ってカイザーテスト(Nihydrin test)を用いて反応程度を点検した。脱保護溶液で、前記のように同様に2回脱保護反応させて、 Pro−Cys−CTLレジンを製造した。DMFとMCとで十分に洗浄し、もう一度カイザーテストを行った後、前記と同様に、下記のアミノ酸付着実験を行った。選定されたアミノ酸配列に基づいて、Fmoc−Arg(Pbf)、Fmoc−Gly、Fmoc−Ile、Fmoc−Ala、Fmoc−Ser(tBu)、Fmoc−Arg(Pbf)、Fmoc−Cys(Trt)、及びFmoc−Ala順に連鎖反応させた。Fmoc−保護基を脱保護溶液で10分ずつ2回反応させた後、よく洗浄して除去した。無水酢酸とDIEA、HoBt(Hydroxybenzotriazole)を入れて1時間アセチル化を行った後、製造されたペプチジルレジンをDMF、MC及びメタノールでそれぞれ3回を洗浄し、窒素空気を徐々に流して乾燥した後、五酸化リン(Phosphorus pentoxide、P2O5)下で真空に減圧して完全に乾燥した後、脱漏溶液[TFA(Trifluroacetic acid)95%、蒸留水2.5%、チオアニソール(Thioanisole)2.5%]30mlを入れた後、常温で時々振りながら2時間反応を保持した。フィルタリングを行ってレジンを濾し、レジンを少量の溶液で洗浄した後、母液と合わせた。減圧を用いて全体ボリュームが半分程度残るように蒸留し、50mlの冷たいエーテルを加えて沈澱を誘導した後、遠心分離して沈澱を集め、2回さらに冷たいエーテルで洗浄した。母液を除去し、窒素下で十分に乾燥して、精製前、NH2−Ala−Cys−Arg−Ser−Ala−Ile−Gly−Arg−Pro−Cys−COOHペプチド1を0.79g(収率:87.7%),NH2−Ala−Cys−Phe−Thr−Arg−Thr−Ser−His−Ala−Cys−COOHペプチド2を0.77g(収率:85.5%),NH2−Ala−Cys−Asp−Gly−Arg−Thr−Gln−Ala−Leu−Cys−COOHペプチド3を0.76g(収率:84.4%)合成した。分子量測定器を用いて測定時に、ペプチド1の分子量1033.3Da(理論値:1033.2Da)、ペプチド2の分子量1096.0Da(理論値:1096.2Da)、ペプチド3の分子量1036.9Da(理論値:1037.1Da)が得られた。
1−1.受容体結合アッセイ(TNFR)
ELISA用プレートに、ペプチド50μg/25μlとコーティングバッファ(20mMリン酸ナトリウム、pH9.6)25μlとを添加して混ぜ、4℃で一晩培養した。PBST(300μl)で3回洗浄した後、ブロッキングバッファ(3%BSA)200μlでブロッキングを2時間室温で実施した。PBST(300μl)で3回洗浄した後、TGFRタイプII(R&D Systems)をウェル当たり0.5μg/1ml添加した後、2時間室温で培養した。PBST(300μl)ずつ3回洗浄した後、抗ヒトIgG−HRP(Santa Cruz Biotechnology)を1:1,000で希釈して、ウェル当たり100μlずつ添加し、2時間室温で培養した。PBST(300μl)で3回洗浄した後、TMB溶液(Sigma Aldrich)を100μlずつ添加した後、発色を進行した。停止溶液(3N H2SO4)50μlを添加して反応を止めた後、O.D 450nmで吸光度を測定した。
マウス大食細胞株であるRaw264.7細胞を1x104細胞/ウェルの密度で48ウェルプレートにシーディングした。24時間安定化した後、6時間無血清培地で培養し、TNF−α 100ng/mlとペプチド50μg/mlとを同時に処理した後、72時間培養した。培養が完了した後、培養上澄み液を除去し、エタノールを用いて細胞を固定化した後、細胞固定が終わった後、PBS(Phosphate Buffer Saline)で3回洗浄した。洗浄溶液を除去した後、比色SRB溶液で処理し、1%酢酸で十分に洗浄を行った後、顕微鏡で細胞を観察して、生存細胞の状態を観察し、20mMトリス(tris)で脱染色された溶液に対して紫外線560nmで吸光度を測定して、細胞の生存状態を測定した。
ヒト毛母細胞(keratinocyte)であるHaCaT細胞を5x105細胞/ウェルで6ウェルプレートにシーディングした後、一晩培養した後、、ペプチドを濃度別に処理し、1時間培養した。細胞を溶解した後、抗pERK抗体(Santa Cruz Biotechnology,米国)と抗p−c−Jun抗体(Santa Cruz Biotechnology,米国)とを用いてRANKL−RANKシグナルであるp−Erk、p−c−Junに対するウェスタンブロッティングを行った。
ヒト単核球(monocyte)THP−1細胞を2x106細胞/ウェルの密度で24ウェルプレートにシーディングした。一晩培養した後、サンプルを10μg/mlの濃度で30分間前処理し、50ng/ml TNF−αを処理した後、24時間培養した。細胞培養培地を獲得し、4℃、13,000rpmで10分間遠心分離した後、上澄み液を分離した。IL−1b及びIL−8ELISAキット(R&D system)を用いてELISAを行った。
2−1.受容体結合アッセイ(HGFR)
ELISA用プレートに、ペプチド50μg/25μlとコーティングバッファ(20mMリン酸ナトリウム、pH9.6)25μlとを添加して混ぜ、4℃で一晩培養した。PBST(300μl)で3回洗浄した後、ブロッキングバッファ(3%BSA)200μlでブロッキングを2時間室温で行った。PBST(300μl)で3回洗浄した後、HGFR(R&D Systems)をウェル当たり0.5μg/1mlを添加した後、2時間室温で培養した。PBST(300μl)で3回洗浄した後、抗ヒトIgG−HRPを1:1,000で希釈して、ウェル当たり100μlずつ添加した後、2時間室温で培養した。PBST(300μl)で3回洗浄した後、TMB溶液を100μlずつ添加した後、発色を進行した。停止溶液(3N H2SO4)50μlを添加して反応を止めた後、O.D 450nmで吸光度を測定した。
2x105細胞/ウェルの細胞密度で6ウェルプレートにMC3T3−E1(マウス骨母細胞株)細胞をシーディングし、一晩培養した細胞を無血清培地で24時間培養した。ペプチドを50μg/mlの濃度で15分処理した(陽性対照群:HGF 50ng/ml)。細胞溶解バッファを処理して溶解物を確保した後、タンパク質を定量し、抗pPI3K抗体(Santa Cruz Biotechnology,米国)を用いてPhospho−PI3K(P−PI3K)に対するウェスタンブロッティングを行った。
ELISA用プレートに、ペプチド50μg/25μlとコーティングバッファ(20mMリン酸ナトリウム、pH9.6)25μlとを添加して混ぜ、4℃で一晩培養した。PBST(300μl)で3回洗浄した後、ブロッキングバッファ(3%BSA)200μlでブロッキングを2時間室温で進行した。PBST(300μl)で3回洗浄した後、BMPR−IB(R&D Systems)をウェル当たり0.5μg/1ml添加した後、2時間室温で培養した。PBST(300μl)ずつ3回洗浄した後、抗ヒトIgG−HRPを1:1,000で希釈して、ウェル当たり100μlずつ添加した後、2時間室温で培養した。PBST(300μl)で3回洗浄した後、TMB溶液を100μlずつ添加した後、発色を進行した。停止溶液(3N H2SO4)50μlを添加して反応を止めた後、O.D 450nmで吸光度を測定した。
2x105細胞/ウェルの細胞密度で6ウェルプレートにMC3T3−E1(マウス骨母細胞株)細胞をシーディングした。一晩培養した細胞を無血清培地で24時間培養した後、ペプチドを50μg/mlの濃度で15分、30分間処理した(陽性対照群:BMP4 50ng/ml)。細胞溶解バッファを処理して溶解物を確保した後、タンパク質を定量し、抗p−Smad1/5/8抗体(Santa Cruz Biotechnology,米国)を用いてPhospho−Smad1/5/8(P−smad1/5/8)に対するウェスタンブロッティングを行った。
マウス骨母細胞株MC3T3−E1細胞を4x104細胞/ウェルで24ウェルプレートにシーディングした後、一晩培養した。50μg/mlアスコルビン酸+10mM b−グリセロリン酸を含んだ培地に取り替え後、各ペプチドを10μg/ml、50μg/mlの濃度で処理し、14日間培養して分化を誘導させた。この際、3日に一回ずつ培地交換及びペプチド処理を繰り返した(陽性対照群:BMP2 30ng/ml)。培養完了したプレートウェルをPBSで2回洗浄した後、アセトン、37%ホルムアルデヒド、クエン酸溶液が混じられた固定バッファで30秒間細胞固定した。白血球アルカリホスファターゼ染色キット(SIGMA)を用いて、下記の染色を進行した。
4x104細胞/ウェルの細胞密度で24ウェルプレートにMC3T3−E1(マウス骨母細胞株)をシーディングした。一晩培養した細胞の培地を50μg/mlアスコルビン酸、10mM β−グリセロリン酸を含んだα−MEM培地に取り替え後、ペプチドを濃度別(10、50μg/ml)に処理し、14日間37℃培養器で培養した。この際、3日に一回ずつ培地交換及びペプチド処理を繰り返した(陽性対照群:30ng/ml rhBMP2(Cell signaling))。培養完了後、プレートウェルをPBSで2回洗浄し、70% EtOHで1時間処理して固定した。次いで、40mMアリザリンレッドS(pH4.2)(Sigma Aldrich)を処理して10分間染色した。10%塩化セチルピリジニウム(10mMリン酸ナトリウムに溶かす(pH7.0))を15分間処理した後、分光光度計(SpectraMax,Molecular Devices)を用いて560nmで吸光度を測定した。
1x105細胞/ウェルの細胞密度で6ウェルプレートにMC3T3−E1(マウス骨母細胞株)をシーディングした。一晩培養した後、ペプチドを濃度別(10、50μg/ml)に処理し、3日間37℃培養器で培養した(陽性対照群:100ng/ml BMP2(Cell signaling))。培養完了した細胞を回収した後、RNA抽出溶液(Easy Blue,Intron)を処理してRNAを準備した後、RTプリミックス(Intron)を使ってcDNAを合成した。各標識因子(OPG、ALP、BSP)に対するプライマーとPCRプリミックス(Intron)とを使ってPCR進行した。
3−1.細胞増殖率観察(proliferation assay)
毛髪主要細胞である真皮乳頭細胞(Human Hair Follicle Dermal Papilla Cell)、毛母細胞(Human Hair Follicle Germinal Matrix Cell)、臍帯静脈内皮細胞(Human umbilical vein endothelial cell)に対する細胞増殖の効果を観察するために、各細胞を96ウェルプレートに3x103細胞/ウェルの密度でシーディングした後、24時間37℃、5%CO2条件下で培養した。血清を完全に除いた同じ培養液で培地を交換した後、ペプチドを濃度別(1μg/ml、10μg/ml、50μg/ml)に処理し、前記と同じ条件で72時間培養した。培養上澄み液を除去し、エタノールを用いて細胞を固定した後、PBSで3回洗浄した。洗浄溶液を除去した後、比色SRB溶液を処理して染色を進行した。1%酢酸で十分に洗浄した後、顕微鏡で細胞を観察して、生存細胞の状態を観察し、紫外線590nmで吸光度を測定して、細胞の生存状態を測定した。
毛髪真皮乳頭細胞で細胞増殖に関与する主要信号伝達物質であるERKリン酸化及びPI3Kに対する発現変化を観察するために、各細胞に、本発明のペプチドを30分、60分間処理した後、これについての特異的な抗体でウェスタンブロッティングを行って、pERK、PI3K変化を観察した。抗pERK抗体(Santa Cruz Biotechnology,米国)及び抗pPI3K抗体(Santa Cruz Biotechnology,米国)を用いて実験を進行した。
毛髪真皮乳頭細胞で毛根成長に関与するタンパク質であるIGF1、KGF、Wnt3aに対する発現の変化を観察するために、各細胞に、本発明のペプチドを24時間処理した後、これについての特異的な抗体でウェスタンブロッティングを行って、毛髪成長関連タンパク質の変化を観察した。
脱毛を誘導するホルモンであるDHT(Dihydrotestosterone)に対するペプチド効能を観察するために、毛髪真皮乳頭細胞にDHT5μg/ml及び本発明のペプチドを濃度別に処理した後、脱毛関連タンパク質であるDKK−1の発現変化を観察した。48時間DHTとペプチドを処理した後、DKK−1に対する特異的な抗体でウェスタンブロッティングを行って、DKK−1の発現を測定した。
配列表の配列番号1または配列表の配列番号3のペプチドが、角質細胞の分化促進誘導を通じて毛髪成長促進効果を示すか否かを観察するために、細胞分化標識物質であるケラチンの発現変化を測定した。
ラットのひげ部位の毛根を分離した後、ペプチドを50μg/mlの濃度で処理して、8日間37℃、5%CO2条件で培養した。5日と8日目の毛髪の長さを観察して、ペプチドの効能を確認した。
Claims (19)
- 配列表の配列番号1、配列表の配列番号2及び配列表の配列番号3のアミノ酸配列で構成された群から選択される1種のアミノ酸配列からなる抗炎症活性を有するペプチド。
- 前記ペプチドは、炎症性サイトカインの発現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、炎症細胞の増殖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。
- 配列表の配列番号1、配列表の配列番号2及び配列表の配列番号3のアミノ酸配列で構成された群から選択される1種のアミノ酸配列からなる骨分化促進活性を有するペプチド。
- 前記ペプチドは、PI3K、Smad1、Smad5、及びSmad8のリン酸化を増加させることを特徴とする請求項4に記載のペプチド。
- 前記ペプチドは、ALP、OPG、及びBSPの発現を増加させることを特徴とする請求項4に記載のペプチド。
- 配列表の配列番号1及び配列表の配列番号2のアミノ酸配列で構成された群から選択される1種のアミノ酸配列からなる発毛促進活性を有するペプチド。
- 前記ペプチドは、毛嚢細胞または臍帯静脈内皮細胞の増殖を促進させることを特徴とする請求項7に記載のペプチド。
- 前記ペプチドは、ERKのリン酸化を増加させることを特徴とする請求項7に記載のペプチド。
- 前記ペプチドは、PI3K、β−カテニン、IGF−1、KGF、及びWnt3aの発現を増加させることを特徴とする請求項7に記載のペプチド。
- 前記ペプチドは、DKK−1の発現を減少させることを特徴とする請求項7に記載のペプチド。
- 請求項1から3のいずれかに記載のペプチドを有効成分として含む抗炎症用組成物。
- 請求項4から6のいずれかに記載のペプチドを有効成分として含む骨分化促進用組成物。
- 前記組成物は、骨疾患の改善または治療に用いられることを特徴とする請求項13に記載の組成物。
- 前記骨疾患は、骨多孔症、少年期骨多孔症、骨形成不全症、骨軟化症、骨壊死症、くる病、骨髄炎、歯槽骨消失、骨ページェット病、高カルシウム血症、原発性副甲状線機能亢進症、転移性骨疾患、骨髄腫、リウマチ性関節炎での骨消失、転移性骨疾患、癌による骨消失、線維性骨異形成症、無形性骨疾患、代謝性骨疾患、または年齢による骨質量の消失を含むことを特徴とする請求項14に記載の組成物。
- 請求項7から11のいずれかに記載のペプチドを有効成分として含む脱毛防止または発毛促進用組成物。
- 有効成分として請求項1から3のいずれかに記載のペプチドを含む組成物を対象に投与する段階を含む炎症疾患の予防または治療方法。
- 有効成分として請求項4から6のいずれかに記載のペプチドを含む組成物を対象に投与する段階を含む骨疾患の予防または治療方法。
- 有効成分として請求項7から11のいずれかに記載のペプチドを含む組成物を対象に投与する段階を含む脱毛予防方法または発毛促進方法。
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CN109970842A (zh) | 2019-07-05 |
CN106488928B (zh) | 2019-05-21 |
US20170049847A1 (en) | 2017-02-23 |
JP2018154642A (ja) | 2018-10-04 |
JP6640916B2 (ja) | 2020-02-05 |
KR101632948B1 (ko) | 2016-06-27 |
EP3360888A1 (en) | 2018-08-15 |
JP2018158929A (ja) | 2018-10-11 |
JP6640915B2 (ja) | 2020-02-05 |
KR20150130617A (ko) | 2015-11-24 |
EP3144317B1 (en) | 2020-03-04 |
EP3360888B1 (en) | 2020-06-24 |
JP6352446B2 (ja) | 2018-07-04 |
EP3144317A4 (en) | 2018-04-25 |
CN106488928A (zh) | 2017-03-08 |
CN109970842B (zh) | 2022-09-13 |
EP3144317A1 (en) | 2017-03-22 |
CN110092815B (zh) | 2023-01-24 |
ES2794579T3 (es) | 2020-11-18 |
EP3360887B1 (en) | 2020-06-17 |
US10238710B2 (en) | 2019-03-26 |
EP3360887A1 (en) | 2018-08-15 |
WO2015174598A1 (ko) | 2015-11-19 |
ES2819897T3 (es) | 2021-04-19 |
CN110092815A (zh) | 2019-08-06 |
ES2821024T3 (es) | 2021-04-23 |
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