JP6560462B2 - 抗肥満及び抗糖尿病効能を有するペプチド及びその用途 - Google Patents
抗肥満及び抗糖尿病効能を有するペプチド及びその用途 Download PDFInfo
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- JP6560462B2 JP6560462B2 JP2018562494A JP2018562494A JP6560462B2 JP 6560462 B2 JP6560462 B2 JP 6560462B2 JP 2018562494 A JP2018562494 A JP 2018562494A JP 2018562494 A JP2018562494 A JP 2018562494A JP 6560462 B2 JP6560462 B2 JP 6560462B2
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 229940007428 victoza Drugs 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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Description
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を反応容器に入れて、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、また溶媒を除去した。反応器に10mlのジクロロメタン溶液を入れて、Fmoc−Ser(tBu)−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て、1時間の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)をDCM(dechloromethane)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、また溶媒を除去した。脱保護溶液(20%のピペリジン(Piperidine)/DMF)10mlを反応容器に入れて、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て、また10分間反応を維持した後、溶液を除去し、各々3分ずつDMFで2回、MCで1回、DMFで1回洗浄して、Ser(tBu)−CTL Resinを製造した。新しい反応器に10mlのDMF溶液を入れて、Fmoc−Lys(Boc)−OH(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を分画で2回に亘って入れた後、全ての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て、1時間の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。脱保護溶液で前記と同様に2回脱保護反応させてLys(Boc)−Ser(tBu)−CTL Resinを製造した。DMFとMCで十分に洗浄し、また1回カイザーテストを遂行した後、前記と同様に以下のアミノ酸付着実験を遂行した。選ばれたアミノ酸配列に基づいてFmoc−Arg(Pbf)−OH、Fmoc−Glu(OtBu)−OH、Fmoc−Lys(Boc)−OHの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時間の間アセチル化を遂行した後、製造されたペプチジルレジンをDMF、MC、及びメタノールで各々3回洗浄し、窒素空気をゆっくり流して乾燥した後、P2O5下で真空に減圧して完全に乾燥した後、脱漏溶液[トリフルオロ化酢酸(Trifluoroacetic acid)95%、蒸溜水2.5%、チオアニソール(Thioanisole)2.5%]30mlを入れた後、常温で時々振り回しながら2時間反応を維持した。フィルタリングを行ってレジンを濾過し、レジンを少量のTFA溶液で洗浄した後、母液と合せた。減圧を用いて全体ボリュームが半分位残るように蒸留し、50mlの冷たいエーテルを加えて沈殿を誘導した後、遠心分離して沈殿を集めて、もう2回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Lys−Glu−Arg−Lys−Serペプチド1を0.77g合成した(収率:89.2%)。分子量測定機を用いて測定時、分子量646.7(理論値段:646.7)を得ることができた。
他の配列番号2のペプチドも前記のような方法により合成を進行した。
本発明のペプチドによる脂肪蓄積抑制効果を測定するために、3T3−L1細胞を2×104細胞/ウェルで24ウェルプレートにシーディングして培養した後、10ug/mlのインスリン、0.1uMのデキサメタゾン、及び0.5uMのIBMXが含まれた分化培地に交換し、濃度別にペプチドを処理した。その後、毎2日毎に10ug/mlのインスリンが含まれた培地に交換し、分化誘導9日目にオイル−レッドO染色アッセイを遂行した。
脂肪細胞は余分のエネルギーを脂肪滴(lipid droplet)の中に中性脂肪の形態に貯蔵してからエネルギーが必要になれば、脂肪トリグリセリドリパーゼ(adipose triglyceride lipase)とHSL、モノグリセリドリパーゼ(monoglyceride lipase)のような酵素により脂肪酸とグリセロールに分解されてエネルギーを生産するか、または細胞信号伝達または脂肪合成に用いる。遊離グリセロール放出の測定は、脂肪細胞に蓄積された中性脂肪の分解効果を評価するためのものである。
Qiagen RNeasy kitを使用して全体RNAを抽出した。RNAから単一鎖DNAを合成するために3mgのRNA、ランダムヘキサマー2mgとDEPCを処理した水を加えて、65℃で5分間反応させた。5×first strand buffer、0.1M DTT、10mM dNTP、逆転写酵素を入れて、総20mlになるようにし、42℃で1時間の間反応させた。また、95℃で5分間加熱した後、蒸溜水20mlを加えて最終40mlのcDNAを作った。PCRは、3mlcのDNA、CGI 58遺伝子に特異的な10pmoleのプライマー、10×Tagバッファ、10mM dNTP、そしてi−Tag DNA合成酵素を混合して施行した。PCR条件は94℃で30秒、55〜56℃で30秒、72℃で30秒に反応させた。サイクル数遺伝子はPCR結果が指数的に増幅できる条件で分析した。PCR産物の5mlを得て1%アガロースゲルに電気泳動し、エチジウムブロマイドで染色して確認して、その結果を図3aから図3cに示した。
マウスの脂肪組織を採取して100mmのディッシュ(DMEM)で一日間培養した後、同一な重量に切って24ウェルプレートに移してペプチドを処理し、48〜72時間の間培養した。各組織の截片を用いてH&E染色を進行した。顕微鏡撮影を通じて得た写真ファイルをImage Jを通じて区画を取って、各区画当たりサイズを比較することができるプログラムを用いて分析した。これを通じて細胞全体個数の面積が分かり、全体個数で割った平均面積も分かる。染色の程度によって結果値が異なるように表現できるが、序盤にしきい(threshold)値を調整して補正することができ、原本ファイルと対照して相対的に少ない面積の細胞は除去後、結果を導出する。
本発明のペプチドが中性脂肪の分解を促進させて脂肪細胞内の脂肪の蓄積を抑制させるメカニズムを調べるためにHSL遺伝子発現に及ぼす効果を調べた。HSL酵素は、脂肪組織で脂肪を分解する時、中性脂肪を遊離脂肪酸とグリセロールに分解する脂肪分解酵素として知られている。
実験動物は6週齢のC57BL/6J miceを中央実験動物(Central Lab. Animal Inc., Seoul, Korea)から購入した後、1週間の間正常食餌により適応期間を有した後、実験に使用した。高脂肪食餌飼料はResearch diets inc.(#product D12492)を用いた。
インスリン抵抗性条件を作るためにTNF−α処理して条件を構成した後、ペプチドを16時間処理後、回収して各因子の変化をRT−PCRで確認して、その結果を図7a及び図7bに示した。RT−PCR遂行条件は実施例3の通りである。
インスリン抵抗性条件を作るためにTNF−α処理して条件を構成した後、ペプチドを16時間処理後、回収して各因子の変化をRT−PCRで確認して、その結果を図8a及び図8bに示した。RT−PCR遂行条件は実施例3の通りである。
Claims (9)
- 配列番号1または配列番号2のアミノ酸配列からなる抗肥満活性または抗糖尿病活性を有する、ペプチド。
- 前記ペプチドは、脂肪細胞内の脂肪の蓄積を減少させ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、脂肪分解を増加させ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、pHSL(phospho−hormone−sensitive lipase)またはCGI−58(Comparative Gene Identification−58)の発現を増加させ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、脂肪細胞の大きさを減少させ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、血糖を減少させ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、アディポネクチン(adiponectin)、GLUT4(Glucose transporter type 4)、IRS−1(Insulin receptor substrate 1)、またはAMPK(AMP−activated protein kinase)−α1の発現を増加させ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または配列番号2のアミノ酸配列からなるペプチドからなる群から選択された1種以上のペプチドを有効成分として含む、肥満の予防または治療用薬剤学的組成物。
- 配列番号1または配列番号2のアミノ酸配列からなるペプチドからなる群から選択された1種以上のペプチドを有効成分として含む糖尿病の予防または治療用薬剤学的組成物。
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