Novel Allosteric Activators for Ferroptosis Regulator Glutathione Peroxidase 4
Novel Allosteric Activators for Ferroptosis Regulator Glutathione Peroxidase 4
复制标题
铁死亡调节剂谷胱甘肽过氧化物酶 4 的新型变构激活剂
DOI：
10.1021/acs.jmedchem.8b00315
复制
发表时间：
2019-01-10
影响因子：
7.3
通讯作者：
Lai, Luhua
中科院分区：
文献类型：
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作者：
Li, Cong;Deng, Xiaobing;Lai, Luhua
谷胱甘肽过氧化物酶4（GPX 4）对于细胞膜修复、炎症抑制和铁凋亡抑制是必不可少的。GPX 4上调为炎症和铁蛋白沉积相关疾病提供了独特的药物发现机会。然而，蛋白质激活剂的合理设计具有挑战性。到目前为止，还没有化合物被报道激活GPX 4的酶活性。在这里，我们确定了一个潜在的变构位点GPX 4，并成功地发现了八个GPX 4激活剂使用一种新的计算策略和实验研究。来自虚拟筛选的化合物1增加GPX 4活性，抑制铁凋亡，减少促炎脂质介质产生，并抑制NF-κ B途径活化。进一步的化学合成和构效关系研究发现了另外七种活化剂。最强的化合物，1d 4，增加GPX 4活性至150%，在20 μ M的无细胞测定和61 μ M的细胞提取物。因此，我们证明GPX 4可以使用化合物直接激活以抑制铁凋亡和炎症。同时，GPX 4激活剂的发现也验证了合理设计变构激活剂的可能性。
Glutathione peroxidase 4 (GPX4) is essential for cell membrane repair, inflammation suppression, and ferroptosis inhibition. GPX4 upregulation provides unique drug discovery opportunities for inflammation and ferroptosis-related diseases. However, rational design of protein activators is challenging. Until now, no compound has been reported to activate the enzyme activity of GPX4. Here, we identified a potential allosteric site in GPX4 and successfully found eight GPX4 activators using a novel computational strategy and experimental studies. Compound 1 from the virtual screen increased GPX4 activity, suppressed ferroptosis, reduced pro-inflammatory lipid mediator production, and inhibited NF-kappa B pathway activation. Further chemical synthesis and structure activity relationship studies revealed seven more activators. The strongest compound, 1d4, increased GPX4 activity to 150% at 20 mu M in the cell-free assay and 61 mu M in cell extracts. Therefore, we demonstrated that GPX4 can be directly activated using chemical compounds to suppress ferroptosis and inflammation. Meanwhile, the discovery of GPX4 activators verified the possibility of rational design of allosteric activators.