Intracellular Delivery of Glutathione Peroxidase Degrader Induces Ferroptosis In Vivo,Angewandte Chemie International Edition

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Intracellular Delivery of Glutathione Peroxidase Degrader Induces Ferroptosis In Vivo
Angewandte Chemie International Edition ( IF 16.1 ) Pub Date : 2022-08-04 , DOI: 10.1002/anie.202206277
Tianli Luo _{1,

2} , Qizhen Zheng _{1,

2} , Leihou Shao _{1,

2} , Tianyu Ma _{1,

2} , Lanqun Mao ₃ , Ming Wang _{1,

2}

Affiliation

A small-molecule protein degrader based on the strategy of proteolysis targeting chimera (PROTAC) was designed to deplete glutathione peroxidase 4 (GPX4) and regulate cancer cell ferroptosis. We demonstrate that a rationally designed GPX4 degrader, dGPX4 shows a five-fold enhancement of ferroptosis induction efficiency compared to that of GPX4 inhibition. Moreover, the intracellular delivery of dGPX4 using a novel type of biodegradable lipid nanoparticles (dGPX4@401-TK-12) induces ferroptosis in vivo to effectively suppress tumor growth without appreciable side effects.

中文翻译：

谷胱甘肽过氧化物酶降解剂的细胞内递送诱导体内铁死亡

一种基于蛋白水解靶向嵌合体 (PROTAC) 策略的小分子蛋白降解剂旨在消耗谷胱甘肽过氧化物酶 4 (GPX4) 并调节癌细胞的铁死亡。我们证明，与 GPX4 抑制相比，设计合理的 GPX4 降解剂 dGPX4 的铁死亡诱导效率提高了五倍。此外，使用新型可生物降解脂质纳米颗粒（dGPX4@401-TK-12）在细胞内递送 dGPX4 可在体内诱导铁死亡，从而有效抑制肿瘤生长而没有明显的副作用。

更新日期：2022-08-04

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