JP6725515B2 - 小分子を用いた鉄欠乏生物における生理機能の回復 - Google Patents
小分子を用いた鉄欠乏生物における生理機能の回復 Download PDFInfo
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- JP6725515B2 JP6725515B2 JP2017534311A JP2017534311A JP6725515B2 JP 6725515 B2 JP6725515 B2 JP 6725515B2 JP 2017534311 A JP2017534311 A JP 2017534311A JP 2017534311 A JP2017534311 A JP 2017534311A JP 6725515 B2 JP6725515 B2 JP 6725515B2
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Description
本明細書に示されているように、必要とする患者に投与される小分子は、鉄トランスポーターを欠く対象において、生理機能を回復させるのに有用であり、ならびに単層を横断するイオンの輸送を回復させる。
a)鉄結合及び輸送の増進を決定する;
b)増殖の回復の増進を決定する;及び
c)ヒト疾患に関連する系(human disease-relevant systems)における生理機能の増進を決定する。
そのような輸送を実施する小分子を同定するために、改良された機能相補実験を実施した。鉄輸送複合体Fet3Ftr1を欠く増殖欠損サッカロミセス・セレビシエ(S.cerevisia)(fet3Δftr1Δ)を用いて、鉄に結合すると思われる小分子をスクリーニングした後、天然物であるヒノキチオール(図1E)が、酵母における公知のシデロフォアトランスポーターと無関係に(図4A)、細胞増殖を回復させた(図1F、1G)。増殖の回復は、好気条件下で生じ(図4B)、細胞内イオンの利用を示唆する。ヒノキチオール処理fet3Δftr1Δ酵母は、類似の倍加時間で(図4C)野生型のレベルまで増殖する(図1H)。増殖回復は、一般的なホルミシス効果によるものではなく(図4D)、ヒノキチオールに対する継続した依存を以って、>40日持続しうる(図4E)。
ヒノキチオールが促進するfet3Δftr1Δ増殖の回復の背後にある基礎をより理解するために、鉄の結合及び輸送を確認した(図5A、5C)。トリス(ヒナコラト)鉄(III)錯体(tris(hinacolato) iron (III) complex)の結晶構造(図5D)は、親水性の鉄結合中心コアを包み込む疎水性の外側シェルを明らかにする。このアッセイで増殖を回復させることができない水溶性イオンキレート剤(図4I、及び図4E、4F)とは反対に、トリス(ヒナコラト)鉄(III)は、オクタノールに優勢的に分配する(図4E、4F)。C2−デオキシヒノキチオール(C2deOHino、図1E)を作成するC−2酸素の合成削除(図5G)は、鉄の結合及び輸送をなくし、これを、ヒノキチオールの生物活性における鉄輸送の役割に関する有力なプローブとする。
ヒト疾患に関連する系において生理機能を回復させるヒノキチオールの能力を評価した。血中への放出及びトランスフェリン媒介の循環の前に、DMT1−依存性非ヘム鉄吸収が十二指腸細胞の微絨毛において生じる。トランスフェリン結合鉄はその後、発達中のエリトロン(developing erythrons)における、サイトゾルへのDMT1媒介エンドソーム鉄放出、及び続くミトコンドリア内への鉄輸送の後、末梢で利用される。DMT1欠損は、鉄吸収の減少及び赤血球前駆細胞におけるヘモグロビン合成の減少を生じさせ、総合して、低色素性小球性貧血を引き起こす。栄養吸収及び赤血球の成熟のDMT1欠損モデルにおいて、ヒノキチオールが、鉄吸収及び細胞内鉄輸送の両方を回復させることができ、結果として、正常な生理機能を回復させることができたと仮説をたてた。
分化Caco−2腸上皮単層におけるヒノキチオール促進経上皮鉄輸送を最初に評価した。安定なshRNAトランスフェクションによってDMT1欠損細胞を確立した(図6A)。十二指腸イオン吸収に見合った条件を用いて、shDMT1単層と比較して、対照の単層の頂端側への55Feの添加は、細胞内への高い55Feの取込み(図2A)及び高い経上皮輸送(図2B)を示した。ヒノキチオール(500nM)を頂端側へ添加すると、単層の一体性を破壊することなく(図2D)、取込み及び輸送の両方が、対照におけるそれらの値(図2C)に類似する割合に回復した(図2A、2B)。ヒノキチオール媒介の取込み及び輸送は、DMT1発現に非依存的であり(図6B)、及び十二指腸全体に亘りみられるpH値の範囲で維持された(図6C)。C2deOHinoは、取込みも輸送も促進させることはできず(図2A、2B)、水溶性鉄キレート剤であるデフェリプロン及びピリドキサールイソニコチノイルヒドラゾン(PIH)でも促進できなかった(図6D)。
ヒノキチオールがDMT1欠損赤血球前駆細胞(erythroid progenitors)においてヘモグロビン合成を回復させる能力を評価した。エキソビボで、DMT1欠損Belgrade(b/b)及び健康な(+/b)ラットから単離した網状赤血球を、59Fe−トランスフェリンを添加した血漿中においてインキュベートして、ヒノキチオールが鉄利用を促進する能力を評価した。ヒノキチオールは、溶血を生じない濃度において用量依存的態様で、ヘムへの59Feの組込みを増加させた(図7A)が、C2deOHinoは明らかな効果を有さなかった。
ヒノキチオールが、インビトロで鉄の吸収及びヘモグロビン合成を回復させる能力を観察した後、DMT1欠損動物における生理機能の回復に関してヒノキチオールを評価した。Belgrade(b/b)ラット(図3A)は、疾患の優れたモデルであり、数あるマーカーの中で、ヘマトクリット値の低下のような、重篤な血液異常を示す。ヒノキチオールは、妥当な薬物動態半減期を有し、健康なラットにおいて比較的毒性がなく(図3B)、及び透過性アッセイは、インビボで良好な経口バイオアベイラビリティを示唆した。ラットの食餌中の(食餌の0.2%)、ヒノキチオール並びに鉄に結合もまたその輸送もしない誘導体であるC2deOHinoへの、b/bラットの慢性曝露を実施した。このヒノキチオールの投与量は、13週間の経口での処置の後、非致死性であることが既に示されており(Y.M. Cho et al., A 13-week subchronic toxicity study of hinokitiol administered in the diet to F344 rats. Food Chem Toxocol 49, 1782-1786 (2011))、毎日合計〜125mg/kgの処置になった。処置の4週間後、ヘマトクリット値に有意な増加が観察され、非貧血状態を示す値を超えた(図3C)。際立って、1ヶ月の処置の後、0.2%ヒノキチオール(〜100mg/kg/日)は、b/bラットのヘマトクリット値を、最早貧血とはみなされないレベルまで回復させた(図9B)が、C2deOHinoは、未処置のb/bラットに普通に観察される低いヘマトクリット値をもたらした。これは、>2ヶ月持続した。
他の鉄トランスポーター欠損の疾患モデルにおける生理機能の回復についてヒノキチオールを評価した。多くのミトコンドリア病は、貧血をもたらす鉄利用障害を生じさせる。例えば、ミトコンドリア内膜にみられるミトフェリンの欠損は、ミトコンドリアマトリックスへの鉄の取込みを減少させる。これは、ヘモグロビンレベルを低下させ、低色素性貧血を生じさせる。したがって、貧血のこの別の原因を治療するためにヒノキチオールを試験した。
ヘモクロマトーシスは、米国における重要な遺伝子疾患であり、FPN1の欠損によって生じうる。FPN1は、腸細胞から血中への鉄の主要なエクスポーターであり、さらに、老化赤血球細胞の赤血球貪食の後に、肝臓の細網内皮系のマクロファージから鉄を放出する役割を果たす。ヒノキチオールが促進する鉄吸収及び細胞内再分布の著しい一般性を観察するために、FPN1欠損系からの鉄の放出を促進することについてヒノキチオールをさらに評価した。
他の実施形態
1.鉄トランスポーターの欠損又は欠陥により特徴づけられる疾患又は状態を治療する方法であって、必要とする対象に、治療有効量の小分子を投与することを含み、それにより、前記疾患又は状態を治療する、方法。
2.前記鉄トランスポーターの欠損又は欠陥により特徴づけられる疾患又は状態が、低色素性小球性貧血である、実施形態1記載の方法。
3.必要とする対象において経上皮鉄輸送を増進させる方法であって、有効量の小分子を前記対象に投与することを含む、方法。
4.必要とする対象において生理機能を増進させる方法であって、有効量の小分子を前記対象に投与することを含む、方法。
5.必要とする対象においてヘモグロビン合成を増進させる方法であって、有効量の小分子を前記対象に投与することを含む、方法。
6.必要とする対象において鉄放出を増進させる方法であって、有効量の小分子を前記対象に投与することを含む、方法。
7.前記小分子は、アムホテリシンB(AmB)、カルシマイシン、ノナクチン、デフェリプロン、プルプロガリン、及びマルトール、並びにそれらの任意の組合せからなる群より選択される、実施形態1−6いずれかに記載の方法。
8.前記小分子は、カルシマイシン、デフェリプロン、プルプロガリン、及びマルトール、並びにそれらの任意の組合せからなる群より選択される、実施形態7記載の方法。
9.前記小分子はヒノキチオールである、実施形態1−6いずれかに記載の方法。
10.前記小分子が全身投与される、実施形態1−9いずれかに記載の方法。
11.前記小分子が経口投与される、実施形態1−9いずれかに記載の方法。
12.前記小分子が静脈内投与される、実施形態1−9いずれかに記載の方法。
13.前記対象は哺乳動物である、実施形態1−12いずれかに記載の方法。
14.前記対象はヒトである、実施形態13記載の方法。
15.前記対象は、二価金属トランスポーター1(DMT1)が欠損している、実施形態1−14いずれかに記載の方法。
16.インビトロで細胞における経上皮鉄輸送、生理機能、又はヘモグロビン合成を増進させる方法であって、前記細胞に有効量の小分子を接触させることを含む、方法。
17.エキソビボで臓器における経上皮鉄輸送、生理機能、又はヘモグロビン合成を増進させる方法であって、前記臓器に有効量の小分子を接触させることを含む、方法。
18.前記小分子は、アムホテリシンB(AmB)、カルシマイシン、ノナクチン、デフェリプロン、プルプロガリン、及びマルトール、並びにそれらの任意の組合せからなる群より選択される、実施形態16又は17記載の方法。
19.前記小分子は、カルシマイシン、デフェリプロン、プルプロガリン、及びマルトール、並びにそれらの任意の組合せからなる群より選択される、実施形態18記載の方法。
20.前記小分子はヒノキチオールである、実施形態16又は17記載の方法。
21.対象において鉄トランスポーターの欠損又は欠陥により特徴づけられる疾患又は状態を治療することができる化合物を同定する方法であって、
a)細胞に小分子を接触させる;及び
b)前記細胞における鉄の結合及び輸送の増加を決定する;
各工程を含み、前記細胞は哺乳動物の疾患又は状態を表わす、方法。
22.細胞増殖の増進又は回復を決定することをさらに含む、実施形態21記載の方法。
23.前記細胞における生理機能の改善又は増進を決定することをさらに含み、前記細胞はヒトの疾患又は状態を表わす、実施形態21又は22記載の方法。
Claims (12)
- 治療有効量の小分子を含む、対象において鉄トランスポーターの欠損又は欠陥により特徴づけられる疾患又は状態を治療するための組成物であって、前記小分子はヒノキチオールである、組成物。
- 前記鉄トランスポーターの欠損又は欠陥により特徴づけられる疾患又は状態が、低色素性小球性貧血である、請求項1に記載の組成物。
- 対象において経上皮鉄輸送を増進させるために使用される、請求項1又は2に記載の組成物。
- 対象において生理機能を増進させるために使用される、請求項1又は2に記載の組成物。
- 対象においてヘモグロビン合成を増進させるために使用される、請求項1又は2に記載の組成物。
- 対象において鉄放出を増進させるために使用される、請求項1又は2に記載の組成物。
- 前記小分子が全身投与される、請求項1−6のいずれか1項に記載の組成物。
- 前記小分子が経口投与される、請求項1−6のいずれか1項に記載の組成物。
- 前記小分子が静脈内投与される、請求項1−6のいずれか1項に記載の組成物。
- 前記対象は哺乳動物である、請求項1−9のいずれか1項に記載の組成物。
- 前記対象はヒトである、請求項10に記載の組成物。
- 前記対象は、二価金属トランスポーター1(DMT1)が欠損している、請求項1−11のいずれか1項に記載の組成物。
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- 2016-01-11 AU AU2016205030A patent/AU2016205030B2/en active Active
- 2016-01-11 US US15/542,596 patent/US11517540B2/en active Active
- 2016-01-11 EP EP16735544.5A patent/EP3242723B1/en active Active
- 2016-01-11 WO PCT/US2016/012855 patent/WO2016112381A1/en active Application Filing
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2022
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US20180263926A1 (en) | 2018-09-20 |
US20230293452A1 (en) | 2023-09-21 |
JP2018504392A (ja) | 2018-02-15 |
AU2016205030B2 (en) | 2021-04-01 |
EP3242723A1 (en) | 2017-11-15 |
US11517540B2 (en) | 2022-12-06 |
WO2016112381A1 (en) | 2016-07-14 |
AU2016205030A1 (en) | 2017-08-03 |
EP3242723A4 (en) | 2018-07-25 |
EP3242723B1 (en) | 2021-10-06 |
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