JP6742999B2 - 環状抗微生物性擬ペプチド及びその使用 - Google Patents
環状抗微生物性擬ペプチド及びその使用 Download PDFInfo
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- JP6742999B2 JP6742999B2 JP2017522966A JP2017522966A JP6742999B2 JP 6742999 B2 JP6742999 B2 JP 6742999B2 JP 2017522966 A JP2017522966 A JP 2017522966A JP 2017522966 A JP2017522966 A JP 2017522966A JP 6742999 B2 JP6742999 B2 JP 6742999B2
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- antimicrobial
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Description
本出願は、参照としてその全体が本明細書に組み込まれる2014年10月31日に出願された欧州特許出願EP14191238号の優先権を主張する。
本明細書全体にわたって、以下の段落中で定義するいくつかの用語が用いられている。
上述のように、本発明は、様々な応用において使用することができる環状抗微生物ペプチドを提供する。強力な抗微生物特性に加えて、本発明の環状抗微生物ペプチドは、ヒト血清中において非常に大きな安定性を示し、ヒト細胞に対する毒性を欠く、具体的にはヒト細胞に対する細胞溶解活性を欠く。
本発明はいくつかの環状抗微生物ペプチドを提供する。本明細書で使用する用語「環状ペプチド」とは、アミノ末端及びカルボキシ末端が共有結合で連結されており、それによって環が生じているポリペプチド鎖をいう。ペプチドが環状であることを示すために、ペプチド配列を角括弧で挟んで示す。
(FFWLSRRTK)(配列番号1、実施例中でPep6と呼ぶ)、
(FFWSRRTK)(配列番号2、実施例中でPep7と呼ぶ)、
(FFWRRTK)(配列番号3、実施例中でPep8と呼ぶ)、
(FFWLRR-ΨHyt-K)(配列番号4、実施例中でPep10)と呼ぶ、
(FFWRR-ΨHyt-K)(配列番号5、実施例中でPep11と呼ぶ)、
(Ψ1Nal-FWRR-ΨHyt-K)(配列番号6、実施例中でPep12と呼ぶ)、
(FF-Ψ1Nal-WRR-ΨHyt-K)(配列番号7、実施例中でPep13と呼ぶ)、
(Ψ2Nal-F-Ψ2Nal-RR-ΨHyt-K)(配列番号8、実施例中でPep14と呼ぶ)、
(FF-Ψ2Nal-RR-ΨHyt-K)(配列番号9、実施例中でPep15と呼ぶ)、
(Ψ2Nal-F-Ψ2Nal-RR-ΨV-K)(配列番号10、実施例中でPep16と呼ぶ)、
(Ψ1Nal-F-Ψ1Nal-RR-ΨGlyco-K)(配列番号11、実施例中でPep17と呼ぶ)、
(FFWRRVK)(配列番号12、実施例中でPep18と呼ぶ)、
(Ψ1Nal-F-Ψ1Nal-RRVK)(配列番号13、実施例中でPep19と呼ぶ)、
(ΨF-F-Ψ1Nal-RR-ΨHyt-K)(配列番号14、実施例中でPep20と呼ぶ)、
式中
ΨHytはアザ-β3-ヒドロキシルスレオニンであり、
ΨVはアザ-β3-バリンであり、
ΨFはアザ-β3-フェニルアラニンであり、
Ψ1Nalはアザ-β3-1-ナフチルアラニンであり、
Ψ2Nalはアザ-β3-2-ナフチルアラニンであり、
ΨGlycoは以下の化学構造(I)を有するグリコール-アミノ酸である。
本発明による環状抗微生物ペプチドは、当業界において公知の様々な適切な方法のうちの任意のものを使用して、たとえば化学合成等によって調製し得る。
その生物活性が理由で、本発明の環状抗微生物ペプチドは、治療的応用を含めた様々な応用において使用し得る。実際、開示されたペプチドは、グラム陽性細菌及びグラム陰性細菌に対して抗微生物活性を示すことが見出されている。グラム陽性細菌及びグラム陰性細菌に属する微生物の詳細な説明は、たとえば「Medical Microbiology」、第3版、1991、Churchill Livingstone、ニューヨーク州中に見つけることができる)。
A.適応症
本発明は、ヒト及びとりわけウマ、イヌ、ネコ、ウシ、ブタ、ラクダ等の他の哺乳動物の両方に関し、人の医学及び獣医学的な治療において適用可能である。
所望の用量の、本発明の環状抗微生物ペプチド(任意選択で1つ又は複数の適切な薬学的に許容される担体又は賦形剤と配合した後)は、それを必要としている対象に、任意の適切な経路によって投与することができる。錠剤、カプセル、注射用溶液、リポソーム内へのカプセル封入、微粒子、マイクロカプセル等の様々な送達系が知られており、本発明の環状抗微生物ペプチドを投与するために使用することができる。投与方法には、これらに限定されないが、真皮、皮内、筋肉内、腹腔内、病巣内、静脈内、皮下、鼻腔内、肺、硬膜外、眼球、及び経口の経路が含まれる。本発明の環状抗微生物ペプチド又はその組成物は、任意の好都合又は他の適切な経路によって、たとえば、輸液又はボーラス注射によって、上皮又は粘膜皮膚の内層を介した吸着によって(たとえば、経口、粘膜、直腸、及び腸管粘膜等)投与し得る。投与は全身性又は局所的であることができる。非経口投与は、カテーテル挿入によって等、患者の所定の組織に向け得る。当業者には理解されるように、本発明の環状抗微生物ペプチドを追加の治療剤と共に投与する実施形態では、環状抗微生物ペプチド及び治療剤は、同じ経路によって(たとえば経口)又は異なる経路によって(たとえば経口及び静脈内)投与し得る。
本発明の環状抗微生物ペプチド(又はその組成物)の投与は、送達される量が意図する目的に有効であるような用量で行う。投与経路、配合、及び投与する用量は、所望の治療効果、処置する疾患の重篤度、患者の年齢、性別、体重、及び全体的な健康状態、使用する環状抗微生物ペプチドの効力、生体利用度、及びin vivo半減期、併用治療の使用(又は使用しないこと)、並びに他の臨床学的因子に依存する。これらの因子は、治療の過程で担当医が容易に決定することができる。その代わりに又はそれに加えて、投与する用量は、動物モデルを使用した研究から決定することができる。これら又は他の方法に基づいて最大の有効性を達成するために用量を調節することは当業界において周知であり、訓練を受けた医師の能力範囲内にある。本発明の環状抗微生物ペプチドを使用した研究が行われるにつれて、適切な用量レベル及び処置期間に関してさらなる情報が明らかとなる。
また、本発明の環状抗微生物ペプチドは、無生物の(生きていない)物体上に細菌汚染が存在しないことが所望される、任意の応用においても使用し得る。そのような無生物の物体の例には、これらに限定されないが、医療装置(たとえば、機器、器具、移植片、コンタクトレンズ、白衣、医療衣、手袋等)、病院内の手術室、研究室、産業施設、公共の場、又は民間住宅における表面(たとえば、床、家具等)が含まれる。
上述のように、治療的応用において、本発明の環状抗微生物ペプチドは、それ自体で又は医薬組成物として投与し得る。したがって、本発明は、有効量の少なくとも1つの環状抗微生物ペプチドと少なくとも1つの薬学的に許容される担体又は賦形剤とを含む医薬組成物を提供する。一部の実施形態では、組成物は1つ又は複数の追加の生物活性剤を更に含む。
注射用調製物、たとえば、無菌的注射用水性又は油性懸濁液は、既知の技術に従って、適切な分散剤又は湿潤剤及び懸濁剤を使用して配合し得る。また、無菌的注射用調製物は、無毒性の非経口的に許容される希釈剤又は溶媒中の無菌的注射用溶液、懸濁液又は乳濁液、たとえば2,3-ブタンジオール中の溶液であってもよい。用い得る許容されるビヒクル及び溶媒の中には、水、リンゲル液、U.S.P.、及び等張塩化ナトリウム溶液がある。更に、無菌的な不揮発性油が溶液又は懸濁媒として慣習的に用いられている。この目的のために、合成モノ又はジグリセリドを含めた任意の無刺激の不揮発性油を用いることができる。また、オレイン酸等の脂肪酸も注射用配合物の調製に使用し得る。無菌的液体担体は、非経口投与のための無菌的な液体形態の組成物において有用である。
特定の実施形態では、本発明の環状抗微生物ペプチドは本発明の医薬組成物中の唯一の活性成分である。他の実施形態では、医薬組成物は1つ又は複数の生物活性剤を更に含む。適切な生物活性剤の例には、これらに限定されないが、抗炎症剤、免疫調節剤、鎮痛剤、抗微生物剤、抗菌剤、抗生物質、抗酸化剤、消毒剤、及びその組合せが含まれる。
また、本発明は、上記で定義した本発明の環状抗微生物ペプチド又はその医薬組成物を含む製品にも関する。製品は、包帯、硬膏剤、縫合糸、接着剤、創傷被覆材、移植片、コンタクトレンズ、洗浄液、保存液(たとえば、コンタクトレンズ又は医療装置用)、洗浄製品(たとえば洗浄パッド又はワイプ)、パーソナルケア製品(たとえば、石鹸、シャンプー、歯磨き粉、日焼け止め、タンポン、オムツ等)、並びに化粧品から選択され得る。
別の態様では、本発明は、本発明の医薬組成物の1つ又は複数の成分を含有する1つ又は複数の容器(たとえば、バイアル、アンプル、試験管、フラスコ、又はボトル)を含んでおり、本発明の環状抗微生物ペプチドの投与を可能にする、薬学的パック又はキットを提供する。
化学薬品。Fmoc保護されたアミノ酸はNovabiochem社及びIris Biotech社(ドイツ、Marktredwitz)からのものであった。H-RinkアミドChemMatrix樹脂はSigma-Aldrich社から、TBTUはIris Biotech社からのものであった。ペプチド合成及びHPLC用の溶媒はCarlo Erba-SdS社(スペイン、Sabadell)からのものであった。TFAはFluorochem Ltd社(英国、Derbyshire)からのものであった。すべての他の化学薬品は、Sigma-Aldrich社から、入手可能な最高品質のものを購入した。Pep C-terはProteogenix社からのものであった。
その発現が細菌細胞質内へ刺激された際、PepA1ペプチドは黄色ブドウ球菌膜内に蓄積され、これらの膜を破壊する(Sayedら、J. Biol. Chem.、2012、287:43454〜43463頁)。興味深いことに、本発明者は、合成したPepA1がグラム陽性細菌(黄色ブドウ球菌)及びグラム陰性細菌(大腸菌)に対して抗細菌活性を示し、これらの2つの細菌に対して8μMの最小阻害濃度(MIC、Table 1(表1))及び16μMの最小殺菌濃度(MBC)を有することを見出した。しかし、ヒト赤血球に対する溶血活性も検出され、これはMICでの20%の溶血に相当することが見出された。
効率的な抗細菌活性を有するペプチドは、一般的にはヒト細胞も破砕し、ヒト及び細菌のペプチダーゼによる加速された分解を受けやすく、それにより、その臨床的使用が制限される。本研究では、ヒト細胞を標的とする強力な細菌毒素を、ヒト赤血球に対する毒性を欠く有効な抗細菌剤へと変換した。開始毒素中では見つからない最適化されたFFWRR配列パターンを有する環状擬ペプチドは、細菌膜の変更及び透過をもたらし、ヒト血清中における安定性は数時間までに実質的にアップグレードされている。
Claims (3)
- 治療的抗微生物剤として使用するための、配列番号2〜14からなる群から選択されるアミノ酸配列を有する環状抗微生物ペプチドを含む組成物。
- 有効量の少なくとも1つの請求項1に定義される環状抗微生物ペプチドと、薬学的に許容される担体又は賦形剤とを含む医薬組成物。
- 包帯、硬膏剤、縫合糸、接着剤、創傷被覆材、移植片、コンタクトレンズ、洗浄液、保存液、洗浄製品、パーソナルケア製品、及び化粧品からなる群から選択される、少なくとも1つの請求項1に記載の環状抗微生物ペプチドを含む、又は請求項2に記載の医薬組成物を含む製品。
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