JP2018150348A - 低色素症の改善及び脂肪形成抑制効能を有するペプチド及びその用途 - Google Patents
低色素症の改善及び脂肪形成抑制効能を有するペプチド及びその用途 Download PDFInfo
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- JP2018150348A JP2018150348A JP2018098359A JP2018098359A JP2018150348A JP 2018150348 A JP2018150348 A JP 2018150348A JP 2018098359 A JP2018098359 A JP 2018098359A JP 2018098359 A JP2018098359 A JP 2018098359A JP 2018150348 A JP2018150348 A JP 2018150348A
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Abstract
Description
(i)本発明の配列表の配列番号1または配列表の配列番号2のアミノ酸配列からなるペプチドは、メラニン生成増加活性及び脂肪生成抑制活性を示す。
(ii)本発明のペプチドは、チロシナーゼの発現を増加させる転写因子であるMITFとMITFの発現を増加させるCREBのリン酸化を増加させて、結果的に、チロシナーゼの発現を増加させ、究極的にメラニン合成を増加させる。
(iii)本発明のペプチドは、細胞内に蓄積された脂肪の量を減少させ、脂肪生成機転に関与するペリリピン及びPPARγの発現を減少させることによって、究極的に脂肪生成を抑制する。
(iv)本発明は、前述したペプチドを含むメラニン低色素症の改善または治療用組成物、及び肥満の治療または予防用薬剤学的組成物を提供する。
合成例1:ペプチド合成
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(dichloromethane)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、ジメチルホルムアミド(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(Resin)を製造した。新たな反応器に10mlのDMF溶液を入れ、Fmoc−Ala(Bachem,Swiss)200mmole、HoBt200mmole及びBop200mmoleを入れた後、撹拌してよく溶かした。反応器に400mmoleのDIEA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最小限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、Ala−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−Ser(tBu)、Fmoc−Arg(pbf)、Fmoc−Phe、Fmoc−Phe、Fmoc−Arg(pbf)、Fmoc−Cys(Trt)、及びFmoc−Gln(Trt)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、P2O5下で真空に減圧して完全に乾燥した後、脱漏溶液[トリフルオロ酢酸(Trifluroacetic acid)81.5%、蒸留水5%、チオアニソール(Thioanisole)5%、フェノール(Phenol)5%、EDT2.5%、及びTIS1%]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TFA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−Gln−Cys−Arg−Phe−Phe−Arg−Ser−Ala−Cys−COOHペプチド1を0.75g合成(収率:86.5%)し、同じ方法でNH2−Tyr−Cys−Arg−Phe−Phe−Asn−Ala−Phe−Cys−COOHペプチド2を0.70g合成した(収率:80.7%)。分子量測定器を用いて測定時に、ペプチド1の分子量1117.0(理論値:1117.3)、ペプチド2の分子量1168.1(理論値:1168.3)が得られた。
6ウェル培養用平板に、メラニン形成細胞(B16F10細胞株)を37℃培養器で24時間培養した後、各板の培地を除去し、新たな培地に取り替えた後、配列表の配列番号1または配列表の配列番号2のアミノ酸配列を有する本発明のペプチドを濃度別に処理する。72時間培養した後、培養液を除去し、細胞を取り外した後、1.5mlチューブに移して、13,000rpmで3分間遠心分離して、上澄み液を除去し、細胞ペレットを回収してメラニンを測定する。細胞ペレットに、2M NaOHを150μlずつ入れて、60℃で30分間細胞内メラニンを溶解させる。96ウェル平板の各ウェルに溶解させて得た上澄み液を100μlずつ入れて、490nmで吸光度を測定する。
メラニン形成細胞(B16F10細胞株)を6ウェル培養用平板に24時間培養後、本発明のペプチドを濃度別に処理する。6時間から24時間まで細胞を培養した後、細胞を溶解してメラニン形成に関与する信号伝逹物質であるCREBリン酸化とMITFの発現をそれぞれの特異的な抗体を用いたウェスタンブロット方法を用いて観察する。抗pCREB抗体(Santa Cruz Biotechnology,米国)と抗MITF抗体(Santa Cruz Biotechnology,米国)とを用いて実験を進行した。
メラニン形成細胞(B16F10細胞株)を6ウェル培養用平板に24時間培養後、本ペプチドを濃度別に処理する。24時間培養した後、細胞を取り外してメラニン形成に関与する酵素であるチロシナーゼ、TRP1に対するそれぞれの特異的なプライマーを用いてRT−PCRで発現の増加を観察する。
メラニン形成細胞(B16F10細胞株)を6ウェル培養用平板に24時間培養後、本発明のペプチドを濃度別に処理する。24時間培養した後、細胞を溶解してメラニン形成に関与する核心酵素であるチロシナーゼの発現を特異的な抗体を用いたウェスタンブロット方法を用いて観察する。抗チロシナーゼ抗体(Santa Cruz Biotechnology,米国)を用いて実験を進行した。
脂肪前駆細胞(3T3−L1細胞株)を24ウェル培養用平板に48時間培養後、分化組成物(0.5mM IBMX、0.25mMデキサメタゾン、10mg/mlインスリン)と共に本発明のペプチドを濃度別に処理して7日間培養する。
脂肪前駆細胞(3T3−L1細胞株)を6ウェル培養用平板に48時間培養後、分化組成物(0.5mM IBMX、0.25mMデキサメタゾン、10mg/mlインスリン)と共に本ペプチドを濃度別に処理して7日間培養する。培養後、脂肪生成機転に関与する遺伝子であるペリリピンとPPARγに対する特異的なプライマーを用いてRT−PCRを進行する。ペリリピンとPPARγのmRNA値が抑制されたか否かを確認する。
Claims (9)
- 配列表の配列番号2のアミノ酸配列からなるメラニン生成増加活性を有するペプチド。
- 前記ペプチドは、MITFの発現及びCREBのリン酸化を増加させる活性を有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、チロシナーゼの発現を増加させる活性を有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2のアミノ酸配列からなる脂肪生成抑制活性を有するペプチド。
- 前記ペプチドは、細胞内に蓄積された脂肪を減少させる活性を有す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、ペリリピン及びPPARγの発現を減少させる活性を有することを特徴とする請求項4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メラニン低色素症の改善または治療用組成物。
- 前記低色素症は、白斑症、白色症、脱色素性母斑、白色粃糠疹、癜風、炎症後脱色症、斑状強皮症、部分的白皮症、特発性滴状低色素症、または点状白皮症であることを特徴とする請求項7に記載のメラニン低色素症の改善または治療用組成物。
- 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肥満の治療用薬剤学的組成物。
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