Reactive Oxygen Species (ROS)-Activatable Prodrug for Selective Activation of ATF6 after Ischemia/Reperfusion Injury.
Reactive Oxygen Species (ROS)-Activatable Prodrug for Selective Activation of ATF6 after Ischemia/Reperfusion Injury.
复制标题
活性氧（ROS）-可激活前药，用于在缺血/再灌注损伤后选择性激活 ATF6。
DOI：
10.1021/acsmedchemlett.9b00299
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发表时间：
2020
影响因子：
4.2
通讯作者：
Cooley,ChristinaB
中科院分区：
文献类型：
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作者：
Palmer,JonathanE;Brietske,BreannaM;Bate,TylerC;Blackwood,ErikA;Garg,Manasa;Glembotski,ChristopherC;Cooley,ChristinaB
我们在这里描述了一种活性氧（ROS）可激活的前药的设计、合成和生物学评价，用于选择性递送小分子ATF6激活剂147，用于缺血/再灌注损伤。合成了ros活化前药1和不能释放游离药物的阴性对照，并检测了过氧化氢介导的活化。prodrug1通过其无法接受er驻留细胞色素P450酶（如Cyp1A2）的代谢氧化而阻断了147的活性，这是首次在这里直接探测到的。原代心肌细胞中ros活化前药1的生物学评价表明，ros对过氧化物介导的毒性具有保护作用，并增强了模拟I/R损伤后的生存能力。在患病条件下选择性靶向ATF6激活的能力，建立了局部应激反应信号通路激活的潜力，作为I/R损伤和相关蛋白质错误折叠疾病的治疗方法。
We describe here the design, synthesis, and biological evaluation of a reactive oxygen species (ROS)-activatable prodrug for the selective delivery of147, a small molecule ATF6 activator, for ischemia/reperfusion injury. ROS-activatable prodrug1and a negative control unable to release free drug were synthesized and examined for peroxide-mediated activation. Prodrug1blocks activity of147by its inability to undergo metabolic oxidation by ER-resident cytochrome P450 enzymes such as Cyp1A2, probed directly here for the first time. Biological evaluation of ROS-activatable prodrug1in primary cardiomyocytes demonstrates protection against peroxide-mediated toxicity and enhances viability following simulated I/R injury. The ability to selectively target ATF6 activation under diseased conditions establishes the potential for localized stress-responsive signaling pathway activation as a therapeutic approach for I/R injury and related protein misfolding maladies.