JP2020111620A - リポ多糖およびリピドaの阻害のためのミエロペルオキシダーゼ組成物および方法 - Google Patents
リポ多糖およびリピドaの阻害のためのミエロペルオキシダーゼ組成物および方法 Download PDFInfo
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- myeloperoxidase
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Abstract
Description
本願は、2016年5月27日に出願された米国仮出願第62/342382号の利益を主張する。
細菌性毒素は、宿主組織を直接損傷することによって、および免疫系を無効にすることによって感染および疾患を促進する。2種類の細菌性毒素:外毒素および内毒素がある。外毒素は、細菌によって分泌され、細菌に応じて種々の症状を生じる。例えば細菌性外毒素は、ジフテリア、破傷風、ボツリヌス症、コレラ、下痢、猩紅熱、毒素ショック症候群および髄膜炎の原因になる。内毒素は、リポ多糖(「LPS」)であり、リポ多糖分子の普遍的な毒性脂質構成成分は、リピドAである。内毒素は、グラム陰性細菌の細胞壁の不可欠な部分であり、細胞死で遊離される。血液中の内毒素の存在は、発熱、下痢、敗血症性ショックならびに腎臓、肝臓、副腎および肺などの内臓の機能喪失を生じる場合がある。
すべての前述の参考文献は、過酸化水素が抗毒素活性のために必要であることを教示している。先行技術は、ミエロペルオキシダーゼが単独で、ハロペルオキシダーゼ活性の非存在下で、内毒素を解毒することに有効であることを教示していない、またはわずかに示唆している。
本開示の発明者は、ミエロペルオキシダーゼがグラム陰性細菌に結合するだけでなく、グラム陰性細菌内毒素(リポ多糖)におよびリピドA(毒性の原因となる内毒素の構成成分)にも結合し、そのような結合がリポ多糖およびリピドAの毒性活性を阻害することを発見した。さらに本開示の発明者は、内毒素リポ多糖/リピドAのミエロペルオキシダーゼ阻害が次亜塩素酸塩または一重項酸素分子のハロペルオキシダーゼ酵素生成を必要としないことを驚くべきことに発見した。先行技術に、ミエロペルオキシダーゼがハロペルオキシダーゼ活性の非存在下で抗リポ多糖(抗内毒素)および抗リピドA剤として有効であることを開示しているものはない。
本概要は、発明を実施するための形態において下にさらに記載される概念の選択を簡潔な形式で紹介するために提供される。本概要は、特許請求される主題の重要な特性を特定することを意図せず、特許請求される主題の範囲を決定する補助として使用されることを意図しない。
特定の実施形態では、例えば以下の項目が提供される。
(項目1)
グラム陰性細菌感染を有するヒトまたは動物対象を処置する方法であって、前記対象におけるグラム陰性細菌感染部位にミエロペルオキシダーゼおよびハロゲン化物を含む組成物を投与するステップを含み、前記組成物が、グラム陰性細菌のリポ多糖内毒素活性を阻害する、方法。
(項目2)
前記組成物が、リポ多糖の毒性構成成分であるリピドAの内毒素活性を阻害する、項目1に記載の方法。
(項目3)
前記組成物が、過酸化物産生オキシダーゼをさらに含む、項目1に記載の方法。
(項目4)
前記オキシダーゼの基質の存在下で前記組成物を投与するステップをさらに含む、項目3に記載の方法。
(項目5)
前記過酸化物産生オキシダーゼが、グルコースオキシダーゼであり、前記基質が、グルコースである、項目4に記載の方法。
(項目6)
前記組成物が、少なくとも2種のアミノ酸をさらに含む、項目3に記載の方法。
(項目7)
前記少なくとも2種のアミノ酸が、グリシン、L−アラニン、D−アラニン、L−アラニン無水物、L−グルタミン、L−グルタミン酸、グリシン無水物、馬尿酸、L−ヒスチジン、L−ロイシン、D−ロイシン、L−イソロイシン、D−イソロイシン、L−リシン、L−オルニチン、D−フェニルアラニン、L−フェニルアラニン、L−プロリン、L−ヒドロキシプロリン、L−セリン、タウリン、L−スレオニン、D−スレオニン、L−チロシン、L−バリン、D−バリン、ベータアラニン、L−ベータホモロイシン、D−ベータホモロイシンなどのベータアミノ酸、3−アミノブタン酸、L−2,3−ジアミノプロピオン酸一塩酸塩、D−2,3−ジアミノプロピオン酸一塩酸塩、L−3−アミノイソ酪酸、D−3−アミノイソ酪酸、エチル3−アミノブチレート、サルコシンメチルエステル塩酸塩およびニペコ酸、またはそのアルキルエステルもしくは薬学的に許容される塩からなる群から選択される、項目6に記載の方法。
(項目8)
前記少なくとも2種のアミノ酸が、グリシン、L−アラニン、D−アラニン、L−アラニン無水物、L−グルタミン、L−グルタミン酸、グリシン無水物、馬尿酸、L−ヒスチジン、L−ロイシン、D−ロイシン、L−イソロイシン、D−イソロイシン、L−リシン、L−オルニチン、D−フェニルアラニン、L−フェニルアラニン、L−プロリン、L−ヒドロキシプロリン、L−セリン、タウリン、L−スレオニン、D−スレオニン、L−チロシン、L−バリンおよびD−バリン、またはそのアルキルエステルもしくは薬学的に許容される塩からなる群から選択される、項目7に記載の方法。
(項目9)
前記組成物が、グリシン、L−アラニン、D−アラニン、L−アラニン無水物、L−グルタミン、L−グルタミン酸、グリシン無水物、馬尿酸、L−ヒスチジン、L−ロイシン、D−ロイシン、L−イソロイシン、D−イソロイシン、L−リシン、L−オルニチン、D−フェニルアラニン、L−フェニルアラニン、L−プロリン、L−ヒドロキシプロリン、L−セリン、タウリン、L−スレオニン、D−スレオニン、L−チロシン、L−バリン、D−バリン、ベータアラニン、L−ベータホモロイシン、D−ベータホモロイシンなどのベータアミノ酸、3−アミノブタン酸、L−2,3−ジアミノプロピオン酸一塩酸塩、D−2,3−ジアミノプロピオン酸一塩酸塩、L−3−アミノイソ酪酸、D−3−アミノイソ酪酸、エチル3−アミノブチレート、サルコシンメチルエステル塩酸塩およびニペコ酸、またはそのアルキルエステルもしくは薬学的に許容される塩からなる群から選択される少なくとも3種のアミノ酸を含む、項目3に記載の方法。
(項目10)
前記少なくとも3種のアミノ酸が、グリシン、L−アラニン、D−アラニン、L−アラニン無水物、L−グルタミン、L−グルタミン酸、グリシン無水物、馬尿酸、L−ヒスチジン、L−ロイシン、D−ロイシン、L−イソロイシン、D−イソロイシン、L−リシン、L−オルニチン、D−フェニルアラニン、L−フェニルアラニン、L−プロリン、L−ヒドロキシプロリン、L−セリン、タウリン、L−スレオニン、D−スレオニン、L−チロシン、L−バリンおよびD−バリン、またはそのアルキルエステルもしくは薬学的に許容される塩からなる群から選択される、項目9に記載の方法。
(項目11)
前記3種のアミノ酸が、グリシン、L−アラニンおよびL−プロリンである、項目10に記載の方法。
(項目12)
前記組成物が、前記オキシダーゼの基質の存在下にある場合、1分間に1mlあたり100pmolから50μmolのペルオシドを生成するために有効な過酸化物産生オキシダーゼを含む、項目3に記載の方法。
(項目13)
前記組成物が、1から50,000μg/mlのミエロペルオキシダーゼを含む、項目1に記載の方法。
(項目14)
前記組成物が、前記少なくとも2種のアミノ酸をそれぞれ0.1から約500mM含む、項目6に記載の方法。
(項目15)
前記組成物が、10から5,000μg/mlのミエロペルオキシダーゼ、0.3から50mMのグリシン、0.3から50mMのL−アラニン、0.3から50mMのL−プロリンおよび1から500U/mlのグルコースオキシダーゼを含む、項目11に記載の方法。
(項目16)
前記ヒトまたは動物対象が、歯肉、眼、耳、皮膚、軟部組織、創傷、膣領域、鼠径部領域、褥瘡または熱傷領域の細菌感染に罹患している、項目1に記載の方法。
(項目17)
細菌感染を有するヒトまたは動物対象を処置する方法であって、ミエロペルオキシダーゼ、過酸化物産生オキシダーゼおよび少なくとも3種のアミノ酸を含む第1の組成物を前記対象の細菌感染部位に投与するステップ;ならびに前記オキシダーゼの基質を含む第2の組成物を前記対象における前記細菌感染部位に投与するステップを含む、前記第1の組成物が、前記第2の組成物との組合せで作用して、グラム陰性細菌によって産生されたリポ多糖内毒素を不活性化する、方法。
(項目18)
前記第1の組成物および前記第2の組成物が、前記感染部位への投与前に混合される、項目17に記載の方法。
(項目19)
前記第1の組成物および前記第2の組成物が、前記感染部位に同時に投与される、項目17に記載の方法。
(項目20)
前記第1の組成物および前記第2の組成物が、前記感染部位に順次投与される、項目17に記載の方法。
本開示は、グラム陰性細菌感染を有するヒトまたは動物対象を処置する方法であって、上記対象におけるグラム陰性細菌感染部位にミエロペルオキシダーゼを含む組成物を投与するステップを含み、上記組成物が、感染部位に存在するリポ多糖およびリピドAを解毒するように作用する、方法を広範に指向する。ミエロペルオキシダーゼ組成物は、リポ多糖(内毒素)およびリピドA(毒性の原因となる内毒素の純化された構成成分)に結合し、解毒できる。
(実施例1)
**0.5mg/ml GOにより40EUの内35が阻害されたことを、1mg GOあたり70EU阻害に外挿す
る
***E101(酵素)およびE101(完全)は、MPOおよびGOを4:1の比で含む。阻害活性をMPO 1mg
あたりで算出する。
(実施例2)
(実施例3)
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US5389369A (en) * | 1991-02-21 | 1995-02-14 | Exoxemis, Inc. | Halo peroxidase containing compositions for killing yeast and sporular microorganisms |
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