JP6348126B2 - 創傷治癒を促進する生物活性短鎖ペプチド - Google Patents
創傷治癒を促進する生物活性短鎖ペプチド Download PDFInfo
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- JP6348126B2 JP6348126B2 JP2015558016A JP2015558016A JP6348126B2 JP 6348126 B2 JP6348126 B2 JP 6348126B2 JP 2015558016 A JP2015558016 A JP 2015558016A JP 2015558016 A JP2015558016 A JP 2015558016A JP 6348126 B2 JP6348126 B2 JP 6348126B2
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Description
本発明は、哺乳動物の傷治癒を促進するのに有用な生物活性短鎖ペプチドに関する。単離ペプチドが標的とする傷は、好ましくは、皮膚及び関連する粘膜表面に影響を及ぼす傷である。どんな具体的機構に限定されるものでないが、本発明のペプチドは、細胞の増殖及び移動を刺激することにより、傷の治癒に影響を及ぼすことができる。本発明のペプチドは、インビトロ及びインビボの両方で有用であり、ケラチノサイトの前記活性を誘起することができる。
米国特許第5,962,410号、第5,861,478号及び第7,696,174号は、本発明を理解する上で有用な開示を提供しており、それらの全体を引用を以て本願に組み込まれるものとする。ペプチドHB107(MPKEKVFLKIEKMGRNIRN)(SEQ ID NO:10)自体は、蛾に存在する抗菌性蛋白質であるセクロピンBのフラグメントを構成する。HB−107は、由来する蛋白質の静菌性効果を示さないが、表皮の傷治癒クォリティを向上させる[Lee et al., 2004]。この19アミノ酸残基ペプチドは、創傷治癒に重要なケラチノサイトの増殖及び移動、スクラッチ傷閉鎖及び抗炎症活性を刺激する多官能性免疫モジュレータである。
HB107の中に位置し、4〜6個の連続アミノ酸残基からなるペプチドの概要を以下に示す。
ヒトの皮膚ケラチノサイト(ATCC CRL-2404)を、無血清ケラチノサイト成長培地の中で成長させた。培地には、ヒト組換体上皮成長因子(EGF)(Life Technologies Corporation, Grand Island, N.Y.)が5ng/ml補給されている。細胞を12ウェルプレートに播種し、100%コンフルエント(confluent)に達することができた。細胞単層を24時間飢餓させた後、P200(200μl)ピペットチップを用いてスクラッチ創傷(scratch wound)を作った。スクラッチ創傷を洗浄し、時間0の時に写真撮影した。ペプチドを加えた。ペプチドの最終濃度は40μg/mlである。細胞は、画像撮影のために短時間室温に置いた以外は、培養器の中に保持した。培養器は、37℃、CO25%、湿度>90%である。スクラッチ創傷の傷口閉鎖は処理後7〜8時間後であり、その結果を表1に示す。
表1は、培養されたケラチノサイトにおけるスクラッチ創傷の傷口閉鎖を示す。処理7時間後のPBS試料の傷口閉鎖を100%とし、PBS試料に対するペプチド試料の傷口閉鎖を算出した。なお、表の中で、*印は顕著(significant)であることを表す。
ペプチドが細胞に対して毒性を有しないことを確認するための試験を行なった。正常なヒトの表皮ケラチノサイトを96ウェルプレートに播種した。プレートは、37℃の温度で、5%CO2の存在下にて、細胞を>95%コンフルエントに成長させた。ペプチドは濃度が、50、100、200及び500μg/mlの保存溶液の中で希釈した。細胞培地を様々な濃度のペプチドを含む新しい培地と取り替えた後、37℃の温度及び5%CO2の条件で24時間培養した。処理の終了時、ATCC(Manassas VA)から購入したMTTアッセイキットを用いて細胞生存率を測定した。結果を表1に示す。MTTアッセイを用いて測定結果では、50〜500μg/mlの濃度で細胞生存率に変化はなかった。
正常なヒトの皮膚ケラチノサイト(ATCC CRL-2404)を、無血清ケラチノサイト成長培地の中で成長させた。培地には、ヒト組換体上皮成長因子(EGF)(Life Technologies Corporation, Grand Island, N.Y.)が5ng/ml補給されている。細胞の検査を、毎日、顕微鏡写真を撮影して行なった。培養物が50〜75%コンフルエントになったとき、プレート内の培養物を吸引し(aspired)、0.25%トリプシン/EDTAを加えた。細胞が球形になり分離されると、新しい培地を加えてトリプシンを中和した。細胞は次に遠心分離され、ペレットは新しい培地の中で再懸濁した。血球計を用いて、懸濁した細胞を計数し、各ウェルに100μlの細胞懸濁液を加えて、細胞の合計数をウェル当たり約500〜1000に調節した。中央の60ウェルを使用し、外側のウェルは蒸発を最少にするために、新しい培地が満たされた。6〜8時間培養後、細胞が各ウェルの中に付着したとき、PBS又はペプチドを所望濃度の2倍含む新しい培地100μlを加えたものを3つ作った。マイクロプレートは、次に、37℃の温度及び5%CO2の条件で48〜72時間培養した。
表2は、本発明ペプチドについて、正常なヒト表皮のケラチノサイト増殖の調節を示す。なお、表の中で、*印は顕著であることを表す。
84遺伝子をエンコードする創傷治癒、細胞外マトリクス及び接着分子を、Sunny Biodiscovery, Inc(Santa Paula, CA)によるPCRアレイを用いて分析した。これは、EPIDERM(登録商標)の代用皮膚は、MatTek(Ashland, MA)により入手し、製造者のインストラクションに基づいて操作した。一晩かけて平衡させた後、培地を変更し、20Gニードルにより10の全層刺創傷を作った。HB2235(330μg/ml)又は対照としての水を皮膚組織の上に塗布したものを2つ作り、2時間処理した。創傷のない正常な組織2つについても対照として用い、創傷と正常組織との間の遺伝子プロファイルを調べた。処理の終わりに、組織を集めて、RNAlater(登録商標)(Ambion, Austin, TX)の安定化溶液の中に保存した。RNAを、Illustra mini RNAspin kit(GE Healthcare, Piscataway, NJ)を用いて抽出し清浄化した。清浄化された全てのRNAを、Agilent HP-8452Aダイオードアレイ分光光度計により260nm及び280nmで評価した。試料全体のRNA濃度を均一にし、対象とする遺伝子の発現を測定した。測定は、1本鎖合成キットと共にPCR arrays PAHS-121Aを使用し、BioRad iCycler iQ Detection Systemを有するリアルタイム定量PCRにより行なった。SYBR Green master mix及びPCRの運転状況はQiagenから得た。5つのハウスキーピング遺伝子に対する遺伝子発現の正規化を、RT2 Profiler PCR Arra Data analysis version 3.5ソフトウエアを用いて行なった後、結果を、EfficiencyΔΔCt法を用いて定量化した。2つの試料において、発現量が合理的に高く(検出するのに30サイクルより少ない)、調節(modulation)が1.5以上のとき、遺伝子の発現量が異なるとみなした。
表3は、選択された遺伝子発現プロファイリングを示しており、創傷皮膚組織と創傷の無い対照との関係、HB2235で処理した創傷と処理していない創傷との関係を、倍率変化(fold change)として表している。
Bergers G, Coussens LM (2000). Extrinsic regulators of epithelial tumor progression: metalloproteinases. Curr Opin Genet Dev. 10: 120-127
Claims (11)
- 単離されたペプチドであって、配列がSEQ ID NO:5(MGRN)又はSEQ ID NO:2(KMGRN)からなり、遊離酸の形態であるか又はカルボキシ末端でアミド化されているか又はアミン末端で脂質化されている、ペプチド。
- ペプチドが、 SEQ ID NO:5(MGRN)又はSEQ ID NO:2(KMGRN)であり、カルボキシ末端でアミド化されているか又はアミン末端で脂質化されている、請求項1のペプチド。
- L−アミノ酸エナンチオマーとD−アミノ酸エナンチオマーのどちらか一方又は両方を含む、請求項1のペプチド。
- 請求項1に記載の少なくとも一種のペプチドと、薬学的に許容される担体とを含む組成物。
- ペプチドは、0.1μg/mL〜500μg/mL、又は0.1μg/mL〜20mg/mLの範囲の濃度で存在する、請求項4の組成物。
- 組成物は、エアロゾル、エマルジョン、液体、ローション、溶液、ゲル、マイクロカプセル、クリーム、ペースト、軟膏、粉末又はフォームの形態である、請求項4の組成物。
- ペプチドが、 SEQ ID NO:5(MGRN)又はSEQ ID NO:2(KMGRN)であり、カルボキシ末端でアミド化されているか又はアミン末端で脂質化されている、請求項4の組成物。
- 哺乳動物の皮膚又は粘膜組織の創傷を治療するために用いられる製剤であって、前記製剤が、ペプチドを含む組成物を含み、前記ペプチドが、SEQ ID NO:4(EKMG)、SEQ ID NO:5(MGRN)又はSEQ ID NO:2(KMGRN)である、製剤。
- ペプチドが、 L−アミノ酸エナンチオマーとD−アミノ酸エナンチオマーのどちらか一方又は両方を含むか、又は担体分子に共役化されているか、アミド化されるか若しくは脂質化されている、請求項8の製剤。
- ペプチドが遊離酸の形態である、請求項8の製剤。
- 創傷が、擦過傷、水疱、火傷、裂傷、潰瘍、打撲、発疹、瘡痕、ストレッチマーク又は老化又は環境曝露に起因する創傷である、請求項8の製剤。
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PCT/US2014/012378 WO2014126681A1 (en) | 2013-02-14 | 2014-01-21 | Short bio-active peptides for promoting wound healing |
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EP3312608B1 (en) * | 2016-10-24 | 2019-10-02 | Akribes Biomedical GmbH | Methods for identifying a non-healing skin wound and for monitoring the healing of a skin wound |
US10232009B1 (en) * | 2017-09-29 | 2019-03-19 | Pro Sunfun Biotech Research And Development Co., Ltd. | Peptide for promoting wound healing, its composition and method of using the same |
CN108586575B (zh) * | 2018-04-11 | 2020-08-14 | 福建省中科生物股份有限公司 | 一种多肽及其皮肤修复功能的应用 |
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