JP2016521746A - 種々の皮膚症状の処置に有用なヒトc−x−cケモカイン由来テトラペプチド - Google Patents
種々の皮膚症状の処置に有用なヒトc−x−cケモカイン由来テトラペプチド Download PDFInfo
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Abstract
Description
本発明は、生物学的、美容的および治療的活性を有するテトラペプチドに関する。特に、本発明は、いくつかのC−X−Cケモカインの保存領域に由来するテトラペプチドに関する。これらのペプチドは、細胞移動、血管形成を促進し、LTAなどの細菌細胞構成成分が誘発する炎症誘発シグナルを中和し、正常上皮皮膚代用物を刺激する活性を示している。本発明はさらに、創傷修復を促進し、皮膚およびその他の関連身体表面、例えば口腔に影響を及ぼす種々の傷害を処置するためにこれらのペプチドを用いる方法に関する。
ケモカインは、創傷治癒、炎症/抗炎症および血管形成/血管新生抑制活性を調節する。それらは、白血球上のGタンパク質共役受容体(GPCR)クラスの受容体および標的組織における細胞表面グリコサミノグリカン(GAG)に結合することにより、それらの機能を発揮する。GAGへのケモカインの結合は、GAG上の負電荷鎖とケモカイン中の塩基性残基のクラスターとの相互作用により生成されるイオン力により媒介される(Handel et al,2005)。in vivoでは、状況はより複雑であり、ケモカインは固定化勾配または走触性勾配を生成することにより働き、これが、炎症の部位への細胞の移動を導くと考えられている(Proudfoot,2006)。GAG−ケモカイン相互作用は細胞外マトリクスに沿った勾配の確立において極めて重要な役割を果たしており、ケモカインがそれらのGタンパク質共役受容体へと結合することを助長し得る。GAGまたは硫酸ヘパリン(HS)プロテオグリカンは、シグナル伝達のための機能性ケモカイン共受容体としても振る舞い、GAG/ケモカインとケモカイン受容体との三元複合体の形成をもたらし得る(Handel et al,2005)。特定のケモカインについての研究により、ケモカインに対するGAGの結合部位がマッピングされた。GRO−アルファ前駆体(CXCL−1)、ケモカイン2前駆体(CXCL−2)、ケモカイン3前駆体(CXCL−3)、ケモカイン4前駆体(CXCL−4)、ケモカイン5前駆体(CXCL−5)、ケモカイン6前駆体(CXCL−6)、IL−8前駆体(CXCL8)、ケモカイン9前駆体(CXCL−9)、ケモカイン11前駆体(CXCL−11)を含む9つのヒトC−X−Cケモカイン前駆体タンパク質の保存GAG結合部位の一次アミノ酸配列の詳細な試験において、特に興味深い保存テトラペプチド領域を見出した。この試験において定義された保存テトラペプチド範囲は、部分的GAG結合領域内に位置する。以下は、選定したヒトC−X−Cケモカイン前駆体のC末端配列のアラインメントの模式図であり、保存された短テトラペプチドを強調している。アラインメントは、NCBIのウェブサイト(ncbi.nlm.nih.gov)上の多重タンパク質配列アラインメントのためのCOBALTプログラムを用いて生成される。アラインメント中の各ケモカインのC末端部分のみが示されており、数字は配列中の開始残基と終端残基である。A. GRO−アルファ前駆体(NCBI寄託番号P09341.1);B. ケモカイン2前駆体(NCBI寄託番号NP_002080.1);C. ケモカイン3前駆体(NCBI寄託番号NP_002081.2);D. ケモカイン4前駆体(NCBI寄託番号P80162.4);E. ケモカイン5前駆体(NCBI寄託番号NP_002985.1);F. ケモカイン6前駆体(NCBI寄託番号NP_002984.1);G. IL−8前駆体(NCBI寄託番号);H. ケモカイン9前駆体(NCBI寄託番号NP_002407.1);I. ケモカイン11前駆体(NCBI寄託番号EAX05774.1)。
本発明のペプチドは、皮膚の創傷を治癒するために用いられ得る。皮膚および粘膜組織傷害は、表皮層が、例えば裂傷、熱傷または水疱により破損されると生じる。損傷は、押し潰しまたは打撲も伴い得るが、これらは表皮の併発性亀裂を伴わない組織傷害を包含する。皮膚感染ならびにある種の慢性疾病、例えば癌および自己免疫疾患も、表皮表面の犠牲を強要し得る。潰瘍、例えば糖尿病に影響を及ぼす潰瘍または褥瘡に関連する潰瘍は、別の型の皮膚傷害である。これらの創傷は、しばしば、全く難治性で、炎症化しており、感染傾向があり、かつ長い治癒過程を要する。潰瘍またはその他の型の慢性創傷の持続性は、血管形成に関する能力減損による治癒および新規血管生成に関与する細胞性過程の不全のためである。血管形成は、低酸素またはその他の刺激に応答した新規毛管網(微小血管)の形成の過程である(Folkman et al,1992)。この過程は、内皮増殖および新血管の出芽を誘導する低酸素内皮および支持周皮細胞の両方からの血管新生因子の局所分泌を伴う。不十分な血管形成は、創傷治癒減損および皮膚潰瘍の一因である(Galiano et al.,2004)。創傷治癒の不全は、一部には、創傷縁でのケラチノサイトが傷を閉鎖するかまたは被覆するために移動しないという事実のために、病変を上皮化することができない結果でもあり得る(Enoch and Price,2004)。皮膚および粘膜創傷の治癒は、一部は、基底ケラチノサイトの活性化により調整される。活性化時に、創傷周囲に配置されたケラチノサイトは移動して、上皮形成と呼ばれる過程において創傷の上に単一層を形成する。慢性創傷の非治癒縁でのケラチノサイトは過増殖性であるが非移動性であり、移動の欠如が上皮形成をできなくして慢性潰瘍の病因における重要な役割を果たしていることが示されている(Harsha et al,2008)。本発明は、皮膚および粘膜組織におけるケラチノサイトに関連した傷害を処置するためにも用いられ得る。「関連粘膜組織」という用語は、皮膚と同様に編成される任意の組織に関し、上皮細胞/ケラチノサイト、例えば、限定されないが、口、鼻、喉、耳、肛門、生殖器および眼の眼瞼結膜に関連した内張り表面を含有する。これらの組織に影響を及ぼし得る、そして本発明のペプチドでの処置を受けることができる創傷または病変/損傷の例は、擦過傷、水疱、熱傷、裂傷、穿刺、潰瘍、打撲傷、発疹および瘢痕である。術後傷も本ペプチドで処置され得る。
実施例
5ng/mlのヒト組換え上皮増殖因子(EGF)(Life Technologies,Grand Island,N.Y.)を補足した無血清ケラチノサイト増殖培地中で、ヒト皮膚ケラチノサイト(ATCC CRL−2404)を増殖させた。細胞を12−ウェルプレート上に植え付けて、100%集密に到達させた。細胞単一層を24時間飢餓状態にし、次いで、P200(200μl)ピペット先端を用いて引掻き傷を作った。引掻き傷を洗浄し、0時間目に写真撮影した。20μg/mlの最終濃度で、ペプチドを添加した。画像を室温で短時間撮影する際以外は、細胞を37℃、5%CO2で湿度>90%にてインキュベーター中に保持する。引掻き傷閉鎖は7〜8時間処置後に観察し、結果を表1に示す。
ペプチドが細胞に対して細胞傷害性でないことを確かめるために、正常ヒト表皮ケラチノサイトを96−ウェルプレートに植え付けた。プレートを5%CO2の存在下で、37℃でインキュベートして、細胞を>95%集密に増殖させた。ペプチドを、50、100、200および500μg/mlの濃度でストック溶液中に希釈する。細胞培地を、種々の濃度でペプチドを含有する新鮮な培地と取り替えて、次に、37℃、5%CO2で24時間インキュベートする。処理終了時に、ATCC(Manassas VA)から購入したMTTアッセイキットを用いて、細胞生存度を測定した。結果を表1に示す。50〜500μg/mlの濃度では、MTTアッセイを用いて測定した場合、ペプチドは細胞生存度を変えない。
Milliporeから購入したin vitro血管形成アッセイキット(In Vitra Angiogenesis Assay Kit)を用いて、血管形成アッセイを実施した。要するに、メーカーの使用説明書に従って、ECMATRIX(商標)溶液を用いてマトリクス層を調製した。ヒト臍帯静脈内皮細胞(HUVEC)(ATCC,Manassas,VA)を、0.1mg/mlのヘパリン(Sigma−Aldrich)、30ug/mlのECGS(Sigma−Aldrich)および10%ウシ胎仔血清(ATCC,Manassas,VA)を補足した完全F12K培地(ATCC,Manassas,VA)中で培養した。細胞を収集し、完全培地中に再懸濁した。ペプチドを、96−ウェルプレート中で約5×103〜1×104細胞/ウェルで細胞と混合した後、重合ECMATRIX(商標)溶液の表面に細胞を植え付けた。プレートを30℃、5%CO2で9〜12時間までの間インキュベートした。倒立光学顕微鏡下で管形成を定期的に検査し、3および5時間間隔で写真撮影して、以下に示すように各パターンに数値を割り当てた。
ヒト表皮ケラチノサイトにおける黄色ブドウ球菌LTA誘導性IL−6刺激。ヒトケラチノサイトを、無血清ケラチノサイト培地中で>80%集密に増殖させた。黄色ブドウ球菌LTA 10ug/mlを、室温で30分、各ペプチド(50μg/ml)とともに予備インキュベートし、次いで混合物をケラチノサイト培養に移した。処理は24時間行った。上清を取り出した。考え得る細胞破砕屑を除去するために短時間スピン後、メーカーの使用説明書に従って、CellSciences(Canton,MA)から購入したELISAキットを用いて、上清をIL−6試験に付した。表3に示されるように、配列番号1〜7はLTAの作用を明らかに中和し、または拮抗してヒト皮膚ケラチノサイトにおけるIL−6発現を刺激する。
5ng/mlのヒト組換え上皮増殖因子(EGF)(Life Technologies,Grand Island,N.Y.)を補足した無血清ケラチノサイト増殖培地中で、正常ヒト皮膚ケラチノサイト(ATCC CRL−2404)を増殖させた。細胞を顕微鏡で毎日観察する。培養が50〜75%集密になったら、プレート中の培地を吸引し、0.25%トリプシン/EDTAを添加する。細胞が丸くなり剥がれるようになったら、新しい培地を添加することによりトリプシンを中和する。次いで、細胞を遠心分離し、ペレットを新しい培地中に再懸濁する。血球計算器を用いて細胞懸濁液を計数し、各ウェルに100μlの細胞懸濁液を添加することにより、細胞の総数を約500〜1000細胞/ウェルに調整する。典型的には、中央の60ウェルを用い、外側のウェルには新しい培地を充填して蒸発を最小限にする。6〜8時間のインキュベーション後に各ウェル中に細胞が付着したら、PBSまたは2×所望濃度のペプチドを含有する新しい培地100μlを、三重反復で添加する。次に、マイクロプレートを、37℃、5%CO2で48〜72時間インキュベートする。
SOR−300−FT(商標)組織を、0.9mlのあらかじめ温めたアッセイ培地を含有する6−ウェルプレートに移し、標準培養条件(37℃、5%CO2)に1時間平衡化した。1時間平衡後、以下のように組織に新しい培地を再添加した:1)24時間の時点に関しては、組織に0.9mlの培地を添加し、2)>24時間の時点に関しては、細胞培養挿入物を洗浄装置(パート#EPI−WSHR、MatTek Corporation)の上部に載せることにより、5mlの培地を組織に添加した。次に、50μlの試験品目を乾癬組織(n=3)に局所適用して、スポンサーにより選択された3つの濃度で、試験品目を培地に添加した。24および48時間時点で、a)組織を300〜400μLのPBSで3回、局所的にすすぎ、b)組織を含有する挿入物を滅菌鉗子でしっかり保持し、PBS中に挿入物を浸漬することにより試験品目を穏やかにすすぎ、挿入物から培地をデカントして、c)すすぎおよびデカント直後に新しい試験品目を組織に再適用した(局所的に50μl)。t=72時間の時点で分析を実施した(3×反復適用)。Qiagen RT2 第一標準キット(カタログ番号330401)を用いて、cDNAを生成した。Qiagen RT2 SYBR Green qPCR Mastermix(カタログ番号330502)およびQiagen RT2プライマーを用いて、相対的な遺伝子発現を測定した。Bio−Rad CFXソフトウェアを用いて、解析を実行した。
細胞外マトリクスおよび接着分子をコードする84の遺伝子を、Sunny Biodiscovery,Inc(Santa Paula,CA)により実行されたPCRアレイを用いて解析した。要するに、EPIDERM(商標)皮膚代替物(カタログ番号#EPI−212)をMatTek(Ashland,MA)から入手し、メーカーの使用説明書に従って取り扱った。一晩の平衡化後、培地を交換して、HB2233(330ug/ml)または水対照を二重反復で皮膚組織の上部に適用し、24時間処理させた。処理終了時に組織を収集してRNAlater溶液(Ambion,Austin,TX)中に保存した。RNAをIllustraミニRNAspinキット(カタログ番号#95017−489、GE Healthcare,Piscataway,NJ)で抽出して精製した。Agilent HP−8452Aダイオードアレイ分光光度計で、260nmおよび280nmにて精製総RNAを評価した。試料を通してRNAの濃度を一律にして、PCRアレイPAHS−121Aを1st標準合成キット、SYBR GreenマスターミックスおよびPCR実行条件(Qiagenから)とともに用いて、BioRad iCycler iQ Detection Systemでリアルタイム定量PCRにより遺伝子の発現を測定した。効率比較Ct(ΔΔCt)法を結果の定量のために用い、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後、RT2プロファイラーPCRアレイデータ解析バージョン3.5ソフトウェアを用いて実行した。発現のレベルが合理的に高く(30サイクル未満で検出)、かつ高低が各二重反復シリーズで1.5以上であった場合、遺伝子は示差的に発現したとみなされた。
Claims (19)
- ペプチド配列(IまたはV)−X1−K−X2(ここで、X1はE、QまたはKであり、X2はM、F、I、W、またはVである)からなる創傷修復および再生活性を示す単離テトラペプチド。
- 配列番号1(IEKM)、配列番号2(VEKF)、配列番号3(IEKI)、配列番号4(IQKI)、配列番号5(IKKW)、配列番号6(IKKV)、または配列番号7(IKKL)である、請求項1記載のテトラペプチド。
- L−およびD−アミノ酸エナンチオマーのいずれかもしくは両方を含み、または担体分子と共役され、アミド化されもしくは脂質付加される、請求項1に記載のテトラペプチド。
- 遊離酸形態である、請求項1に記載のテトラペプチド。
- 少なくとも1つの請求項1〜4のいずれか1項に記載のテトラペプチドおよび製薬上許容可能な担体を含む組成物。
- 前記テトラペプチドが約0.1μg/mL〜約500μg/mL、または約0.1μg/mL〜約20mg/mLの範囲の濃度で存在する、請求項5に記載の組成物。
- エアゾール、乳濁液、液体、ローション、溶液、ゲル、マイクロカプセル封入物、クリーム、ペースト、軟膏、粉末もしくは発泡体の形態であるか、または皮膚の表面もしくは皮膚組織下への適用のために適合されるデバイス中に組み入れられる、請求項5に記載の組成物。
- 治療的有効量で有効時間適用される場合、哺乳動物における創傷を治癒するかまたは炎症性皮膚症状を処置するのに用いるための組成物であって、前記医薬品が製薬上許容可能な担体および少なくとも1つの請求項1〜4のいずれか1項に記載のテトラペプチドを含む組成物。
- 前記創傷または炎症性症状が前記哺乳動物の皮膚または関連粘膜組織に影響を及ぼす、請求項8に記載の組成物。
- 前記創傷が擦過傷、水疱、熱傷、裂傷、潰瘍、打撲傷、発疹、皮膚伸展線条、瘢痕、伸展裂創もしくは加齢もしくは環境性曝露の作用のためであり、または前記炎症性症状が乾癬、アトピー性皮膚炎および酒さのためであるか、もしくは脱毛もしくは懸垂繊維腫の除去のための使用のためである、請求項9記載の組成物。
- スキンケア処置に用いるための請求項5〜10のいずれか1項に記載の組成物。
- 化粧品に用いるための請求項5〜10のいずれか1項に記載の組成物。
- 皮膚または関連粘膜組織の創傷または炎症性症状を処置するための医薬品の製造のための請求項1〜10のいずれかに記載のテトラペプチドまたは組成物の使用。
- 前記創傷が擦過傷、水疱、熱傷、裂傷、潰瘍、打撲傷、発疹、皮膚伸展線条、瘢痕、伸展裂創もしくは加齢または環境性曝露の作用のためであり、または前記炎症性症状が乾癬、アトピー性皮膚炎および酒さのためであるか、もしくは脱毛もしくは懸垂繊維腫の除去のための使用のためである、請求項13記載の使用。
- 哺乳動物における皮膚創傷を処置するかまたは炎症性皮膚症状を処置するための方法であって、製薬上許容可能な担体および少なくとも1つの請求項1記載のテトラペプチドを含む医薬品を皮膚または関連粘膜組織に投与することを包含する方法。
- 前記テトラペプチドが配列番号1(IEKM)、配列番号2(VEKF)、配列番号3(IEKI)、配列番号4(IQKI)、配列番号5(IKKW)、配列番号6(IKKV)、または配列番号7(IKKL)である、請求項15記載の方法。
- 前記テトラペプチドがL−およびD−アミノ酸エナンチオマーのいずれかもしくは両方を含み、または担体分子と共役され、アミド化されもしくは脂質付加される請求項15記載の方法。
- 前記テトラペプチドが遊離酸形態である、請求項15に記載の方法。
- 前記創傷が擦過傷、水疱、熱傷、裂傷、潰瘍、打撲傷、発疹、皮膚伸展線条、瘢痕、伸展裂創、もしくは加齢もしくは環境性曝露の作用のためであり、または前記炎症性症状が乾癬、アトピー性皮膚炎および酒さのためであるか、もしくは脱毛もしくは懸垂繊維腫除去のための使用のためである、請求項15記載の使用。
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