JP2022535918A - 生理活性ペプチドおよびそれらを含む組成物 - Google Patents
生理活性ペプチドおよびそれらを含む組成物 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1021—Tetrapeptides with the first amino acid being acidic
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/74—Biological properties of particular ingredients
- A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
- A61K2800/782—Enzyme inhibitors; Enzyme antagonists
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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Abstract
Description
X-DAsn-DVal-DVal-DLys-Y(I)
(式中、
Xは、アスパラギンのN末端に連結したアシル基-CO-(CH2)nCH3であり、nは0~20の間の範囲の整数であり、かつ
Yは、リジンのC末端の-OH基を表すか、またはリジンのC末端に連結したアミン基-NR1R2であり、R1およびR2は、互いに等しいかまたは異なり、Hとアルキル基-(CH2)mCH3との間から選択され、mは0~2の間の範囲の整数である)
を有する、D系列のみのアミノ酸からなるテトラペプチドである。
H3C-CO-DAsn-DVal-DVal-DLys-NH2(配列番号1)、および
H3C-(CH2)14-CO-DAsn-DVal-DVal-DLys-NH2(配列番号2)。
ペプチドAc-DAsn-DVal-DVal-DLys-NH2(配列番号1)の合成
以下およびコードAAT11RIで図1にも示される本発明による標記のペプチドを、樹脂Rink-Amide AMおよび9-フルオレニル-メトキシカルボニル/tert-ブチル戦略(Fmoc/tBu)を使用して、固相ペプチド合成(SPPS)によって手動で調製した。最終アミノ酸を樹脂に付着させた後、ペプチドを無水酢酸を用いてN末端でアセチル化し、次いで、TFA:H2O:TIS:EDT(94:2.5:1:2.5)の混合物を用いて固体支持体から脱離した。
新生児ヒト皮膚線維芽細胞(NHDF)は、Lonzaから入手した。成人皮膚線維芽細胞の培養物は、PaniらJ.Alzheimer’s Dis.(2009)18:829-41に記載されているように、異なる年齢の健康なドナー、C6(36歳男性)、C3(57歳女性)およびC12(84歳女性)の皮膚生検から調製した。1983年に概説されているように、Careggi University Hospital(フィレンツェ、イタリア)の倫理委員会および1975年のヘルシンキ宣言によって示されたガイドラインに従って、これらの皮膚細胞を使用するための書面によるインフォームドコンセントを、関与する全てのドナー対象から入手した。全ての細胞培養物を、実験開始時に6から9までの同様の数のステップに供し、5%のCO2を含有する加湿インキュベーター中、37℃で、FBS 10%(Gibco)、100単位/mlのペニシリンG、0.05mg/mlのストレプトマイシンおよびグルタミン2mM(PAN-Biotech GmbH)を添加した改変ダルベッコイーグル培養培地(DMEM、Lonza)中で保存した。
細胞生存率アッセイを、試験製造業者(Promega)の指示に従って、上記処理の72時間後に、96ウェルマイクロプレート(8,000細胞/ウェル)でのMTS細胞増殖試験を用いて行った。全ての細胞培養物は、処理後にそれらの初期生存率を維持していた。
各細胞試料について上記のようにして得られた30~40μgのタンパク質溶解物を、標準的な変性および還元条件下で、4~12%のドデシル硫酸ナトリウム(Bis-Tris Plus BOLT、Invitrogen)を用いたポリアクリルアミドゲル上での電気泳動分離に供し、次いで、これらをポリフッ化ビニリデン膜(PVDF、Millipore)に転写した。コラーゲンIおよびGAPDHタンパク質(後者はロードコントロールとして使用)を、一次ポリクローナルウサギ抗体:抗コラーゲンI型、ab34710、Abcam;抗GAPDH、14C10(Cell Signaling Technology)およびペルオキシダーゼにコンジュゲートした適切な二次抗体(Sigma-Aldrich Chemicals)を用いた免疫組織化学法によって決定した。セイヨウワサビペルオキシダーゼ(Millipore)のImmobilon(商標)基質を用いた増強化学発光手順を使用することによってタンパク質バンドを可視化し、Quantity-Oneソフトウェア(Bio-Rad)を用いたデンシトメトリー分析によって免疫反応性バンドを定量化した。各密度測定値を、対応するGAPDHレベルを内部対照として使用することによって正規化した。
Claims (12)
- 式(I)
X-DAsn-DVal-DVal-DLys-Y(I)
(式中、
Xは、アスパラギンN末端に連結したアシル基-CO-(CH2)nCH3であり、nは0~20の間に含まれる整数であり、かつ
Yは、リジンC末端の-OHであるか、またはリジンC末端に連結したアミノ基-NR1R2であり、R1およびR2は、互いに等しいかまたは異なり、Hとアルキル基-(CH2)mCH3との間から選択され、mは0~2の間に含まれる整数である)
を有するペプチド誘導体。 - Yが-NR1R2である場合、R1およびR2が共にHである一般式(I)を有する、請求項1に記載のペプチド。
- nが0である一般式(I)を有する、請求項1または2に記載のペプチド。
- nが14である一般式(I)を有する、請求項1または2に記載のペプチド。
- H3C-CO-DAsn-DVal-DVal-DLys-NH2(配列番号1)およびH3C-(CH2)14-CO-DAsn-DVal-DVal-DLys-NH2(配列番号2)から選択される、請求項1に記載のペプチド。
- 請求項1から5に定義されるペプチド誘導体を調製する方法であって、第1のアミノ酸を固体支持体上に固定化するステップと、引き続いて、第2~第4のアミノ酸の各々を一般式(I)の同じ順序で添加するステップと、引き続いてAsn N末端でアシル化するステップと、場合により、引き続いてLys C末端でアミド化するステップとを含む方法。
- 少なくとも請求項1から5に定義される一般式(I)のペプチド誘導体と、1種または複数の化粧品として許容される賦形剤、アジュバントまたは担体とを含む化粧品組成物。
- 前記化粧品として許容される賦形剤、アジュバントまたは担体が、香料、着色剤、湿潤/保湿剤、保存剤、機能性成分および/または強調表示成分、溶媒、およびこれらの混合物から選択される、請求項7に記載の化粧品組成物。
- 局所施用のための、セラム、ローション、クリーム、ゲル、軟膏またはムースの形態である、請求項7または8のいずれか一項に記載の化粧品組成物。
- 皮膚に請求項7から9に定義される化粧品組成物を塗布するステップを含む、皮膚老化の徴候を予防および処置するための化粧方法。
- 少なくとも請求項1から5に定義される一般式(I)のペプチド誘導体と、1種または複数の薬学的に許容される賦形剤、アジュバントまたは担体とを含む医薬組成物。
- 美容外科手術後の皮膚の局所処置に使用するための、請求項11に定義される医薬組成物。
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