APP-Mint2のタンパク質間相互作用をペプチドベースの阻害剤と標的化すると,アミロイドβの形成が減少する

Christian R O Bartling^1,2, Thomas M T Jensen¹, Shawna M Henry²

¹Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 162, DK-2100 Copenhagen, Denmark.

Journal of the American Chemical Society

|January 5, 2021

まとめ

ミント2タンパク質は,アルツハイマー病 (AD) のアミロイドβ (Aβ) 産生を促進する. この相互作用を阻害剤や遺伝的手法で標的化することは,ADの有望な治療戦略です.

科学分野:

神経科学
分子生物学
薬物の発見

背景:

アルツハイマー病 (AD) は症状をコントロールし進行を止めるための新しい治療法を必要としています
アミロイド前駆体タンパク質 (APP) の分裂によるアミロイドベータ (Aβ) ペプチドの蓄積がADの特徴である.
Aβ生成におけるミント2タンパク質の役割は議論されており,その効果に関する報告は矛盾している.

研究の目的:

ミント2がアミロイド前駆体タンパク質 (APP) 処理とAβ生成における役割を明らかにする.
APPとMint2のタンパク質相互作用 (PPI) を調査する.
APP-Mint2の相互作用を対象とした新しい治療戦略を開発する.

主な方法:

APP-Mint2のタンパク質-タンパク質相互作用 (PPI) の詳細な分析は,バックボーンH結合とサイドチェーン相互作用の探査による.
APP-Mint2相互作用のための安定した高親和性ペプチド阻害剤の開発.
アルツハイマー病のニューロンインビトロモデルを使用してAβレベルを評価する.

主要な成果:

この研究では,APPとMint2の特定の相互作用が明らかにされました.
APP- Mint2 PPIを標的とした細胞浸透性ペプチド阻害剤は,Aβ42レベルを著しく低下させた.
APP結合欠陥のMint2変種も,in vitroでAβ42濃度の低下をもたらした.

結論:

Mint2は病原性Aβペプチドの形成を促進する役割を果たします.
ミント2タンパク質を遺伝子または薬理学的手段で標的にすることは,アルツハイマー病におけるAβレベルを低下させるための有効な治療法です.
この研究は,新しいアルツハイマー病の治療薬の開発の基盤となる.

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