3-Difluoroalkyl Quaternary Oxindoles Inhibit Macrophage Pyroptosis by Blocking Inflammasome Recruitment of Caspase-1
3-Difluoroalkyl Quaternary Oxindoles Inhibit Macrophage Pyroptosis by Blocking Inflammasome Recruitment of Caspase-1
复制标题
3-二氟烷基季羟吲哚通过阻断 Caspase-1 炎症小体的募集来抑制巨噬细胞焦亡
DOI：
10.1021/acsmedchemlett.0c00070
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发表时间：
2020
影响因子：
4.2
通讯作者：
Lou Xin
中科院分区：
文献类型：
--
作者：
Xiao Qi;Yu Jin-Sheng;Wang Yufang;Ma Danjun;Zhou Jian;Lou Xin
炎症反应的失调是许多使人衰弱和代价高昂的疾病的关键驱动因素，包括免疫紊乱、癌症和感染。焦亡是一种高度炎性的程序性细胞死亡形式，由各种刺激触发，并由炎性半胱天酶的激活介导。为研究和临床实践提供调节焦亡策略的药理学制剂仍然非常有限。在目前的研究中，我们确定了3-二氟烷基季氧吲哚作为caspase-1的化学抑制剂，caspase-1是驱动caspase焦亡的酶。我们的研究结果表明，化合物6可以直接结合到前caspase-1的CARD结构域，抑制其炎症小体募集，并且化合物6对脓毒症模型中焦亡细胞的药理学抑制部分有效。因此，化合物6是一种潜在的治疗炎症性疾病的药物，也是进一步研究炎症在人类健康和疾病中的作用的工具。
Dysregulation of the inflammatory response is a key driver of many debilitating and costly diseases including immune disorders, cancer, and infection. Pyroptosis is a highly inflammatory form of programmed cell death, triggered by various stimuli and meditated by the activation of inflammatory caspases. Pharmacologic agents that provide strategies to modulate pyroptosis for research and clinical practice are still very limited. In current study, we identify 3-difluoroalkyl quaternary oxindoles as chemical inhibitors of caspase-1, the pyroptosis driving caspase. Our results demonstrated compound6could directly bind to the CARD domain of pro-caspase-1 to inhibit its infammasome recruitment and pharmacologic inhibition of pyroptotic cell death by compound6is partially efficacious in sepsis models. Compound6is thus a potential therapeutic for inflammatory disorders and a tool for further study of the inflammation in human health and disease.