JP2021530515A - 鉄欠乏症および関連する貧血を治療するためのエンテロバクチンの新規使用のための方法、システムおよび組成物 - Google Patents
鉄欠乏症および関連する貧血を治療するためのエンテロバクチンの新規使用のための方法、システムおよび組成物 Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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- A—HUMAN NECESSITIES
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- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- Coloring Foods And Improving Nutritive Qualities (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
この国際PCT出願は、2018年7月19日に出願された米国仮特許出願第62/700,480号の利益および優先権を主張する。上に参照された出願の明細書および図面全体が、参照によりその全体が本明細書に組み込まれる。
一実施形態では、本願発明者らは、動物発育に対するE.coli遺伝子の影響を試験するための独自かつ感度の高いアッセイを示す。特に、本願発明者らは、共生細菌によって産生されるシデロホア(エンテロバクチン、またはEnt)が宿主生理学に及ぼす影響に関する新しいパラダイムを特定した。本願発明者らは、Entが、宿主動物におけるミトコンドリア鉄レベルを促進し、宿主発育に有益な影響を与えることを発見した。Entは、宿主ミトコンドリアATPシンターゼのαサブユニットに結合することによってこの機能を実施し、この結合は、ATPシンターゼ複合体全体とは独立している。この以前には未知の機構は、細菌Entの除去の役割と、宿主の不安定な鉄プールに対するその影響と対立する場合があり(図7)、この機能は、微生物と動物との間の共生関係を強化すべきである。C.elegansとヒトとの間のこの機能の保存に起因して、本発明は、両動物種の腸内のエンテロバクテリアの高罹患率、および哺乳動物における共存E.coliがEntを産生する能力と一致し得る。この新規な本発明技術は、微生物と宿主細胞との間の競争(鉄の「取り合い」)に関する新しいパラダイムを示し、このことは、病原性細菌に対する防御機構としてEntに結合する十分に研究された哺乳動物リポカリン2の機能とは異なる(図7)。
1.鉄欠乏症の治療を必要とする対象においてそれを行う方法であって、治療有効量のエンテロバクチン(Ent)、またはまたはその薬学的に許容される塩を投与することを含む、方法。
2.上述の治療有効量のEntは単離される、実施形態1に記載の方法。
3.上述の治療有効量のEntは、上述の治療有効量のEntアナログを含む、実施形態1に記載の方法。
4.上述のEntアナログは、TRENCAM、SERSAM、SER(3M)SAM、TRENSAMおよびTREN(3M)SAMからなる群から選択される、実施形態3に記載の方法。
5.上述のEntまたは上述のEntアナログが、薬学的に許容される担体と混ぜ合わせられる、実施形態1または4に記載の方法。
6.上述の薬学的に許容される担体は、栄養補助食品である、実施形態5に記載の方法。
7.上述の鉄欠乏症は、鉄欠乏性貧血を含む、実施形態1に記載の方法。
8.上述の鉄欠乏症の治療を必要とする上述の対象が、ヒト対象を含む、実施形態1および7に記載の方法。
9.鉄欠乏症の予防を必要とする対象においてそれを行う方法であって、予防有効量のエンテロバクチン(Ent)、またはまたはその薬学的に許容される塩を投与することを含む、方法。
10.上述の治療有効量のEntは単離される、実施形態9に記載の方法。
11.上述の治療有効量のEntは、上述の治療有効量のEntアナログを含む、実施形態9に記載の方法。
12.上述のEntアナログは、TRENCAM、SERSAM、SER(3M)SAM、TRENSAMおよびTREN(3M)SAMからなる群から選択される、実施形態11に記載の方法。
13.上述のEntまたは上述のEntアナログが、薬学的に許容される担体と混ぜ合わせられる、実施形態9または14に記載の方法。
14.上述の薬学的に許容される担体は、栄養補助食品である、実施形態13に記載の方法。
15.上述の鉄欠乏症は、鉄欠乏性貧血を含む、実施形態9に記載の方法。
16.上述の鉄欠乏症の予防を必要とする上述の対象が、ヒト対象を含む、実施形態9および15に記載の方法。
17.対象における鉄欠乏症の治療のための治療剤であって、以下の一般式(I)で表される活性成分
と、薬学的に許容される担体とを含む、治療剤。
18.上述の治療有効量の式Iの化合物は単離される、実施形態17に記載の方法。
19.上述の治療有効量の式Iの化合物は、上述の治療有効量の式Iの化合物のアナログを含む、実施形態17に記載の方法。
20.式Iの化合物の上述のアナログは、
21.上述の式I〜VIの化合物が、薬学的に許容される担体と混ぜ合わせられる、実施形態17または20に記載の方法。
22.上述の薬学的に許容される担体は、栄養補助食品である、実施形態21に記載の方法。
24.上述の鉄欠乏症は、鉄欠乏性貧血を含む、実施形態17に記載の方法。
25.上述の鉄欠乏症の治療を必要とする上述の対象が、ヒト対象を含む、実施形態17および24に記載の方法。
26.上述の栄養補助食品が、プロバイオティクス細菌を含む、実施形態6、14および22に記載の方法。
27.鉄欠乏症の治療を必要とする対象においてそれを行うための遺伝子組換えプロバイオティクス細菌であって、エンテロバクチン(Ent)の生合成のための1つ以上の遺伝子をコードするプロモータに作動可能に連結された異種ヌクレオチドを発現するように構成されたプロバイオティクス細菌を含む、遺伝子組換えプロバイオティクス細菌。
28.上述のプロバイオティクス細菌は、エンテロバクタープロバイオティクス細菌を含む、実施形態27に記載の遺伝子組換え細菌。
29.Entの生合成のための1つ以上の遺伝子をコードするプロモータに作動可能に連結された上述の異種ヌクレオチドは、entA entB、entC、entD、entE、entFからなる群から選択される遺伝子のうちの1つ以上をコードするプロモータに作動可能に連結された異種ヌクレオチドを含む、実施形態27に記載の遺伝子組換え細菌。
31.Entの生合成のための1つ以上の遺伝子をコードするプロモータに作動可能に連結された上述の異種ヌクレオチドは、配列番号1〜6からなる群から選択されるアミノ酸配列のうちの1つ以上をコードするプロモータに作動可能に連結された異種ヌクレオチドを含む、実施形態27に記載の遺伝子組換え細菌。
31.鉄欠乏症の治療を必要とする上述の対象がヒト対象である、実施形態27に記載の遺伝子組換え細菌。
32.上述の鉄欠乏症は、鉄欠乏性貧血を含む、実施形態31に記載の遺伝子組換え菌。
33.鉄欠乏症の治療を必要とする対象においてそれを行うための栄養補給組成物であって、エンテロバクチン(Ent)の生合成のための1つ以上の遺伝子をコードするプロモータに作動可能に連結された異種ヌクレオチドを発現するように構成されたプロバイオティクス細菌と、賦形剤と、を含む、栄養組成物。
34.上述のプロバイオティクス細菌は、エンテロバクタープロバイオティクス細菌を含む、実施形態33に記載の栄養組成物。
35.Entの生合成のための1つ以上の遺伝子をコードするプロモータに作動可能に連結された上述の異種ヌクレオチドは、entA、entB、entC、entD、entE、entFからなる群から選択される遺伝子の1つ以上をコードするプロモータに作動可能に連結された異種ヌクレオチドを含む、実施形態33に記載の栄養組成物。
36.Entの生合成のための1つ以上の遺伝子をコードするプロモータに作動可能に連結された上述の異種ヌクレオチドは、配列番号1〜6からなる群から選択されるアミノ酸配列のうちの1つ以上をコードするプロモータに作動可能に連結された異種ヌクレオチドを含む、実施形態33に記載の遺伝子組換え細菌。
37.上述の鉄欠乏症の治療を必要とする対象がヒト対象である、実施形態33に記載の栄養組成物。
38.上述の鉄欠乏症は、鉄欠乏性貧血を含む、実施形態37に記載の栄養組成物。
本発明技術の一実施形態では、本願発明者らは、宿主動物の成長および発育に利益をもたらす微生物代謝産物の同定を容易にするための独自のアッセイを作製した。本願発明者らによる以前の研究は、熱殺菌(HK)E.coliが、C.elegansの幼虫の成長に総合的に必要とされる特定の分子を欠いていることを明らかにした。HK E.coliプレートに、単独では虫の成長を補助することができなかった生存E.coliを微量追加したとき、幼虫の成長が回復し(図1A)、このことは、微量の生存細菌が、HKフードを使用可能にする代謝産物を生成したことを示唆している。この独自の供給条件を使用して、潜在的に宿主動物に利益をもたらすために特定の代謝産物を提供することができないことに起因して、正常な虫の成長を補助することができないE.coli変異体を検索した。E.coli単一遺伝子ノックアウトライブラリ(E.coli Keio集合)をスクリーニングした後、本願発明者らは、エンテロバクチン(Ent)生合成が破壊された5つのE.coli変異体のいずれかを微量供給された虫が、顕著に遅く成長することがわかった(図1B、C)。驚くべきことに、本願発明者らは、虫の成長欠陥が、Entの餌補給によって完全に克服されることを観察した(図1Dおよび図8A)。さらに、代謝中間体2,3−DHBAを補給すると、entA−E.coliに対する虫の成長を助けたが、entF−E.coliに対する虫の成長を助けず(図1C、E)、このことは、最終産物であるEntのみが、虫に対してこの利益をもたらすことができることを確認する。
Entは、Fe3+に対する高い親和性を有するため、鉄の恒常性に影響を与えることによって宿主動物の成長および発育に潜在的に利益をもたらし得る。本願発明者らは、一般的に使用される蛍光細胞透過性染料であるカルセインAMを使用し、その放射が鉄の結合によって消光され、既に記載されているように生存虫に適用し、宿主中の全鉄レベルを推定した。entA−またはentF−変異体細菌が供給された虫は、蛍光強度が劇的に増加したことによって明らかにされるように、かなり低い鉄レベルを有し、その鉄レベルは、Ent補給によって回復した(図2A)。本願発明者らは、鉄貯蔵タンパク質フェリチンのC.elegansホモログをコードする鉄応答性遺伝子ftn−2の発現も調べた(Romney et al.、2011)。pftn−2::GFPレポーターの発現は、entA−またはentF−変異体細菌が供給された虫において、劇的に減少した(図2B)。したがって、細菌Entは、宿主C.elegansにおいて、鉄レベルを上昇させる。
虫の鉄恒常性に対するEntの影響の根底にある機構を理解するために、本願発明者らは、固定されたEntを用いたアフィニティクロマトグラフィー、その後に質量分光分析を使用して、虫におけるEnt結合タンパク質を同定した(図3A)。2つの独立した実験(図3Aおよび表1)の両方において、2つの候補タンパク質CTL−2およびATP−1のみが捕捉された。CTL−2は、鉄に結合することが既知であるカタラーゼのホモログである。ATP−1は、鉄の生物学における役割は未知のミトコンドリアATPシンターゼのα−サブユニットである(JungeおよびNelson、2015)。次いで、本願発明者らは、動物の成長に対するEntの影響について、各タンパク質の必要性を試験した。atp−1のRNAiは、ctl−2とは異なり、Ent補給による虫の成長の救出を防止し(図3B)、このことは、ATP−1が、CTL−2とは異なり、宿主における観察されたEnt機能を媒介する際に潜在的に重要な役割をはたし得ることを示唆している。
次に、本願発明者らは、EntがEnt−ATP−1複合体を介して宿主の鉄プールを促進するかどうかを試験した。本願発明者らは、第1に、カルセイン−AM蛍光の増加によって示されるように、ATP−1機能喪失(lf)C.elegans変異体、またはatp−1(RNAi)で治療された野生型虫において鉄レベルが劇的に減少したことを示すことによって、鉄恒常性におけるATP−1の役割を決定した(図4A、B)。次いで、本願発明者らは、atp−1のRNAiが、entF−変異体細菌に対するEnt補給で見られる鉄レベルの上昇を排除したため、虫において鉄レベルを促進する際のEntの効果が、ATP−1に依存すると判断した(図4C)。成長が停止した動物に対するHK E.coli+/−Entの効果(図2C)も、atp−1に依存することが見出された(図4D)。最後に、宿主の鉄レベルは、ATPシンターゼの3つの他のサブユニットの各々のRNAiノックダウンによって有意に変化せず(図4B)、このことは、鉄レベルに対するATPの影響が、ATPシンターゼ機能を破壊する間接的な効果に起因する可能性が低いことを示唆している。したがって、細菌Entは、ATPシンターゼα−サブユニットとの相互作用によって、宿主の鉄恒常性を促進する。
ATPシンターゼα−サブユニットとして、ATP−1は、この大きな酵素複合体のβおよび他のサブユニットと相互作用すると予想される。免疫染色を使用して、本願発明者らは、ミトコンドリアにおける哺乳動物ATPシンターゼのα−サブユニット(ATP5A1)およびβ−サブユニット(ATP5B)の同時局在化を観察した(図11A)。ATPシンターゼの本質的な役割と一致して、atp−1およびatp−2の両方における機能喪失変異は、C.elegansにおけるL1停止表現型を示す(図4A)。atp−1またはatp−2のRNAiは、成長欠陥も示した(図11B、C)。したがって、宿主の鉄プールを促進する際のATP−1機能がATPシンターゼの他のサブユニットに依存するかどうかを試験した。Entに対するATP−1の結合が、ATPシンターゼのβ−サブユニットのRNAi(ATP−2)によって影響を受けないことを見出し(図11C)、図4Bに示すように、atp−1(RNAi)によって生じる鉄レベルの低下は、β、bおよびOサブユニットについての遺伝子のRNAiで治療された虫ではみられなかった。したがって、ATP−1のこの役割は、他のATPシンターゼサブユニットとは独立している。
ミトコンドリアへの鉄輸送は、不安定な鉄プールおよび全体的な鉄の恒常性に重大な影響を及ぼすため、本願発明者らは、細菌Entおよびその宿主ATP−1との相互作用がミトコンドリアにおいて鉄レベルを促進するかどうかを決定したいと考えた。本願発明者らは、第1に、ミトコンドリアにおけるATP−1機能と一致する、腸内のATP−1とMitoTrackerマーカーの共局在化を観察した(図12A)。次いで、本願発明者らは、哺乳動物細胞の公開されたプロトコル(Devireddy et al.、2010)から改変されたインビボアッセイを実施し、ミトコンドリアの鉄レベルの促進におけるEnt−ATP−1相互作用の役割を調べた。虫をRNAiで治療し、55FeCl3+/−Entを供給し、続いてミトコンドリアの単離および放射能の測定(55Fe)を行った。ミトコンドリア鉄(55Fe)は、Entを補給すると3倍に増加し、この増加は、ATP−1に依存したが、他のATPシンターゼサブユニットには依存しなかった(図5A)。これに加えて、本願発明者らは、野生型E.coliが供給された虫から単離されたミトコンドリアが、entF−変異体細菌が供給された虫よりも有意に高レベルのシデロホアを含有することを示し、このことは、Entもミトコンドリアに入り(図5B)、ATP−1がRNAiによって減少したときに、ミトコンドリアにおけるEntのレベルが有意に減少した(図5C)ことを示している。したがって、細菌Entは、宿主ミトコンドリアの鉄レベルの増加を容易にし、このプロセスは、宿主ミトコンドリアにおけるATP−1の新規なATPシンターゼに依存しない機能を必要とする。
ATPシンターゼα−サブユニットは、ミトコンドリアマトリックス内に存在し、このタンパク質は、十分に特性決定されたミトコンドリアタンパク質輸送機構によってミトコンドリアに輸送される。したがって、ATP−1が、輸送前にATP−1がEntに結合することを必要とする「共輸送」モデルによって、Ent−Fe3+をミトコンドリアに入り込ませることを容易にする可能性がある。このモデルを試験するために、本願発明者らは、ATP−1合成またはミトコンドリアへのシャトルが存在しない、精製されたミトコンドリアにおけるEntおよびATP−1の役割を観察することが可能であるかどうかを決定したいと考えた。
配列アラインメントは、C.elegans由来のATPシンターゼα−サブユニット(ATP−1、Wormbase;配列番号7)とヒト由来のATPシンターゼα−サブユニット(ATP5A1、NCBI;配列番号8)との間の78%の同一性を示す(図11D)。CAS染色を用い、本願発明者らは、培地に補給されたEntが、ヒトHEK293T細胞に入ることができることを観察した(図6A)。このEnt−ATP−1機能が哺乳動物において保存されているかどうかを試験するために、本願発明者らは、+/−ビオチン−Entを培養したヒトHEK293T細胞由来の全タンパク質抽出物を用い、既に記載したビオチン−Entプルダウンアッセイ(図3A)を繰り返した。ATP5A1が明確に検出され(図6B)、このことは、Entが、哺乳動物細胞中でATP5A1にも結合することを裏付けている。インビトロ結合アッセイでは、ビオチン−Entがヒトタンパク質ATP5A1に直接結合し、この結合が、過剰な遊離Entの存在によって、効率的に競合した(図6C)。第3のアッセイにおいて、本願発明者らは、細胞溶解物+/−Entに放射性標識した鉄(55FeCl3)を添加し、次いで、ATP5A1抗体を用い、IPを行った。Entの存在により、ATP5A1−IP試料における55Feレベルが増加した(図6D)。まとめると、これらのデータは、EntとATPシンターゼα−サブユニットとの間の相互作用が哺乳動物細胞において保存されていることを示している。
図2Gにおいて、本願発明者らは、鉄欠乏条件下で鉄を生存C.elegansに移動させるための強力なEntの効果を示した(鉄キレート剤を添加した)。ここで、ヒトHEK293細胞において同様の試験を行った。鉄キレート剤であるデフェロキサミン(DFO)を培地に添加すると、カルセインAM染色蛍光の増加によって示されるように、鉄レベルが細胞内で有意に減少した。鉄レベルは、培地にEnt(1.5uM)を添加することによってほとんど回復した。Ent添加によるカルセインAM蛍光の減少(45%)は、図6Gに示されるDFOを使用しない試験よりも強く、このことは、低鉄条件が、Entの存在に対して、より感度が高いことを示唆している。この結果は、鉄(低レベルの遊離イオンまたはDFOに結合した鉄)を細胞に移動させる際のEntの有効性を示す。
本願発明者は、合成リポソームを使用して、Entが鉄を脂質二重層を横断して移動させる能力をインビトロで試験している。簡潔に述べると、FeCl3+/−Ent(1.5uM)を、市販脂質(Avanti Lipids)から形成された新鮮なリポソームに添加した。確立された方法によって、ATPSα(ATP−1またはATP5A1)をリポソームに添加した。図19に示すように、リポソームに会合するFe3+のレベルを、以下の2つの方法によって測定した。(A)カルセインAM染色。カルセインAM染料をリポソーム+/−ATPSαに添加し、リポソームの蛍光強度を測定した。(B)リポソームを放射性標識Fe3+(55FeCl3)と共にインキュベートし、リポソームの放射能(相対CPM)を測定した。方法(A)は、カルセインAMがリポソーム内部にのみあるため、リポソーム内の鉄を測定する。方法(B)は、リポソームの外側の鉄を除外しない場合がある、より単純な方法である。各試験において、Entの存在は、(A)内部または(B)リポソームと会合したいずれかの鉄のレベルを明らかに増強した。
本願発明者らは、3週齢の雌マウスに鉄欠乏餌(IDD)(または対照餌)を6週間供給し、貧血を誘導した(ヘモグロビン測定により確認)。次いで、マウス(1群あたり5匹)を、2週間にわたる経口摂取(2日に1回)によって、+/−Ent(2濃度)または+/−FeSO4で処理した。一般に図20A〜Bに示すように、IDDを供給すると、ヘモグロビンおよび鉄レベルが両方とも劇的に低下した。Ent補給は、エラーバーは大きいものの、ヘモグロビンレベルを部分的にではあるが有意に回復し、このことは、重度の貧血状態での鉄取り込み効率の向上におけるEntの役割の可能性を示唆している。Ent添加により、脾臓では鉄レベルが上昇したが、肝臓では上昇しなかった。市販のキット(BioAssay system)を使用して、ヘモグロビンレベルを得た。通常の条件下では、腸から吸収された鉄の約70%がヘモグロビンを生成するために使用され、鉄が過剰である場合、わずかな割合のみが肝臓または他の体細胞組織に貯蔵され得る。貧血条件下では、ミトコンドリアに入った鉄(次いでヘムに結合)の大きな割合が赤血球形成につぎこまれ得る。したがって、Ent補給が肝臓の鉄レベル(鉄貯蔵)に与える影響がほとんどみられなかったことは予想外であった。
本願発明者らは、3週齢の雄マウスに鉄欠乏餌(IDD)(または対照餌)を5週間供給し、貧血を誘導した。次いで、飲料水に加えたIDD+/−Entをさらに2週間供給した。新鮮なEnt希釈水溶液を週に1回提供した。一般的に図21に示されるように、鉄を十分に含む対照餌(CD)を連続的に供給したマウスを対照として含めた。ヘモグロビンレベルを、Hemavet Blood Analyzerによって測定した。平均値±SDを示す。Ent補給は、貧血マウスにおけるヘモグロビンレベルを有意に改善した。その後、試験で使用した脱イオン水(pH5.5)においてEntが非常に不安定であることが判明したため(図25参照)、この試験ではEntの効果が低下した可能性が高い。今後の試験では、pH調整水にEntを投与し、安定性を確保するためにEntのより頻繁な新鮮な希釈を含む。
本願発明者らは、4.5週齢の雄マウスを、鉄欠乏餌(IDD)についての一致した対照である、上述の鉄を十分に含む対照餌(CD)で治療した。上の図20および21に示すように、この食事を供給したマウスは、相対的に正常なヘモグロビンおよび鉄レベルを有していた。図22にさらに示すように、飲料水(pH5.5)においてEntを補給するとき、マウスは増加した成長速度を有していた。この実験は、ヘモグロビンおよび鉄レベルを測定しなかったため不完全であり、これを繰り返す予定である。しかしながら、本願発明者らは、EntがC.elegansにおける幼虫の成長に顕著な役割を有すること、その効果が、動物における鉄レベルの増加を促進する能力に起因することを既に示しているため(図1および2)、体重増加データは依然として意義がある。
一般的に図23に示されるように、(A)5週齢の雌無菌(GF)マウスを、単一の非病原性E.coli(K12)株、野生型またはentF−(Ent欠乏E.coli)でコロニー形成した。マウスの成長(体重増加)を次の4週間測定した。EntF−E.coliでコロニー形成された無菌(GF)マウスは、野生型E.coliでコロニー形成されたマウスと比較して遅い成長を示した。興味深いことに、体重増加の差は、コロニー形成後の最初の2週間で最大であった。(BおよびC)最終的なマウスの鉄レベルは、脾臓のみで有意に低かった(約35%)が、肝臓または他の組織では有意に低くなく、このことは、図20でみられる結果と一致している。鉄レベルを測定した。(D)Ent補給は、entF(−)E.coliでコロニー形成したGFマウスにおける成長の遅れを克服する。entF−細菌でコロニー形成したGF雌マウスに、Entを補給した[週に1回、飲料水(pH5.5)に2濃度を添加]。
本願発明者らの確立されたアッセイ(QiおよびHan、2018)に従って、図24に示されるように、新たに孵化したC.elegans幼虫に、野生型K12 E.coli、または示したシデロホアを補給したentF−E.coliを供給した。このアッセイでは、C.elegansの成長を支えるためにEntが必要である。虫の体積を3日後に測定した(図1に記載の実験について行ったように)。エンテロバクチン補給は、entF−でみられる成長欠陥を回復するが、試験した他の5つのシデロホアは、効果を示すことができない(図1Gの他の結果と一致する)。したがって、鉄輸送および動物発育を促進するためのEntの役割は、Entに固有である。
C.elegans株および管理。線虫のストックを、細菌(E.coli OP50)を播種した線虫成長培地(NGM)プレート上で、20℃で維持した。以下の株/対立遺伝子は、Caenorhabditis Genetics Center(CGC)から得た。N2 Bristol(野生型と呼ばれる)、VC2824:H28O16.1(ok2203)I/hT2[bli−4(e937)let−?(q782)qIs48](I;III)。XA6901:qaEx6901[ftn−2p::pes−10::GFP::his+lin−15(+)]、SJ4103:zcIs14[myo−3::GFP(mit)]。Prpl−28:atp−1(del)導入遺伝子について、ATP結合配列(残基198〜205:DRQTGKTA)を欠失した全コード領域をpPD95.77にクローニングし、ユビキタスRPL28プロモータによって駆動し、次いで、5ng/ul注射マーカー(pCFJ90)を有する10ng/ulプラスミドをatp−1(lf)変異体(VC2824)に注入した。
表
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配列同定情報
Claims (37)
- 鉄欠乏症の治療を必要とする対象においてそれを行う方法であって、治療有効量のエンテロバクチン(Ent)、またはまたはその薬学的に許容される塩を投与することを含む、方法。
- 前記治療有効量のEntは単離される、請求項1に記載の方法。
- 前記治療有効量のEntは、前記治療有効量のEntアナログを含む、請求項1に記載の方法。
- 前記Entアナログは、TRENCAM、SERSAM、SER(3M)SAM、TRENSAMおよびTREN(3M)SAMからなる群から選択される、請求項3に記載の方法。
- 前記Entまたは前記Entアナログが、薬学的に許容される担体と混ぜ合わせられる、請求項1または4に記載の方法。
- 前記薬学的に許容される担体は、栄養補助食品である、請求項5に記載の方法。
- 前記鉄欠乏症は、鉄欠乏性貧血を含む、請求項1に記載の方法。
- 前記鉄欠乏症の治療を必要とする前記対象が、ヒト対象を含む、請求項1および7に記載の方法。
- 鉄欠乏症の予防を必要とする対象においてそれを行う方法であって、予防有効量のエンテロバクチン(Ent)、またはまたはその薬学的に許容される塩を投与することを含む、方法。
- 前記治療有効量のEntは単離される、請求項9に記載の方法。
- 前記治療有効量のEntは、前記治療有効量のEntアナログを含む、請求項9に記載の方法。
- 前記Entアナログは、TRENCAM、SERSAM、SER(3M)SAM、TRENSAMおよびTREN(3M)SAMからなる群から選択される、請求項11に記載の方法。
- 前記Entまたは前記Entアナログが、薬学的に許容される担体と混ぜ合わせられる、請求項9または14に記載の方法。
- 前記薬学的に許容される担体は、栄養補助食品である、請求項13に記載の方法。
- 前記鉄欠乏症は、鉄欠乏性貧血を含む、請求項9に記載の方法。
- 前記鉄欠乏症の予防を必要とする前記対象が、ヒト対象を含む、請求項9および15に記載の方法。
- 前記治療有効量の前記式Iの化合物は単離される、請求項17に記載の方法。
- 前記治療有効量の前記式Iの化合物は、前記治療有効量の前記式Iの化合物のアナログを含む、請求項17に記載の方法。
- 前記式I〜VIの化合物が、薬学的に許容される担体と混ぜ合わせられる、請求項17または20に記載の方法。
- 前記薬学的に許容される担体は、栄養補助食品である、請求項21に記載の方法。
- 前記鉄欠乏症は、鉄欠乏性貧血を含む、請求項17に記載の方法。
- 前記鉄欠乏症の予防を必要とする前記対象が、ヒト対象を含む、請求項17および23に記載の方法。
- 前記栄養補助食品が、プロバイオティクス細菌を含む、請求項6、14および22に記載の方法。
- 鉄欠乏症の治療を必要とする対象においてそれを行うための遺伝子組換えプロバイオティクス細菌であって、エンテロバクチン(Ent)の生合成のための1つ以上の遺伝子をコードするプロモータに作動可能に連結された異種ヌクレオチドを発現するように構成されたプロバイオティクス細菌を含む、遺伝子組換えプロバイオティクス細菌。
- 前記プロバイオティクス細菌は、エンテロバクタープロバイオティクス細菌を含む、請求項26に記載の遺伝子組換え細菌。
- Entの生合成のための1つ以上の遺伝子をコードするプロモータに作動可能に連結された前記異種ヌクレオチドは、entA entB、entC、entD、entE、entFからなる群から選択される遺伝子のうちの1つ以上をコードするプロモータに作動可能に連結された異種ヌクレオチドを含む、請求項26に記載の遺伝子組換え細菌。
- Entの生合成のための1つ以上の遺伝子をコードするプロモータに作動可能に連結された前記異種ヌクレオチドは、配列番号1〜6からなる群から選択されるアミノ酸配列のうちの1つ以上をコードするプロモータに作動可能に連結された異種ヌクレオチドを含む、実施形態26に記載の遺伝子組換え細菌。
- 前記鉄欠乏症の治療を必要とする前記対象がヒト対象である、請求項26に記載の遺伝子組換え細菌。
- 前記鉄欠乏症は、鉄欠乏性貧血を含む、請求項30に記載の遺伝子組換え菌。
- 鉄欠乏症の治療を必要とする対象においてそれを行うための栄養補給組成物であって、エンテロバクチン(Ent)の生合成のための1つ以上の遺伝子をコードするプロモータに作動可能に連結された異種ヌクレオチドを発現するように構成されたプロバイオティクス細菌と、賦形剤と、を含む、栄養組成物。
- 前記プロバイオティクス細菌は、エンテロバクタープロバイオティクス細菌を含む、請求項32に記載の栄養組成物。
- Entの生合成のための1つ以上の遺伝子をコードするプロモータに作動可能に連結された前記異種ヌクレオチドは、entA entB、entC、entD、entE、entFからなる群から選択される遺伝子の1つ以上をコードするプロモータに作動可能に連結された異種ヌクレオチドを含む、請求項32に記載の栄養組成物。
- Entの生合成のための1つ以上の遺伝子をコードするプロモータに作動可能に連結された前記異種ヌクレオチドは、配列番号1〜6からなる群から選択されるアミノ酸配列のうちの1つ以上をコードするプロモータに作動可能に連結された異種ヌクレオチドを含む、請求項32に記載の遺伝子組換え細菌。
- 前記鉄欠乏症の治療を必要とする対象がヒト対象である、請求項32に記載の栄養組成物。
- 前記鉄欠乏症は、鉄欠乏性貧血を含む、請求項36に記載の栄養組成物。
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