PES Derivative PESA is a Potent Tool to Globally Profile Cellular Targets of PES.
PES Derivative PESA is a Potent Tool to Globally Profile Cellular Targets of PES.
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DOI：
10.1016/j.bmcl.2022.128553
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发表时间：
2022-01
影响因子：
2.7
通讯作者：
Jieqiong Yang;Zhenyan Liu;S. Perrett;Hong Zhang;Z. Pan
中科院分区：
文献类型：
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作者：
Jieqiong Yang;Zhenyan Liu;S. Perrett;Hong Zhang;Z. Pan
PES（2-苯乙炔磺酰胺、pifithrin-μ、PFTμ）是一种亲电子化合物，具有抗癌特性，可预防化疗中化疗引起的周围神经病变，并具有免疫调节、抗炎和抗病毒活性。 PES 通常对肿瘤细胞表现出比非肿瘤细胞更高的细胞毒性。 PES 的作用机制尚不清楚，但可能涉及蛋白质的共价修饰，因为 PES 已被发现是 Hsp70 的共价抑制剂。我们开发了一种带有末端炔基的新型 PES 衍生物 PESA，用于进行基于点击反应辅助活性的蛋白质分析（点击反应 ABPP），并用其筛选 PES 的细胞靶点。我们发现PES及其衍生物PES-Cl和PESA与GSH和Hsp70进行迈克尔加成反应的能力相当，并且表现出相似的细胞毒性。通过荧光成像和蛋白质组学研究，我们在 DOHH2 细胞中鉴定出了 300 多种 PESA 附着蛋白。一些参与癌症相关氧化还原过程的蛋白质，例如过氧化还原蛋白 1 (PRDX1)，在质谱检测中显示出更高的频率和丰度。我们的结果表明，PES 及其衍生物的细胞毒性可能与蛋白质硫醇和细胞 GSH 的攻击导致细胞氧化还原稳态破坏有关。这项研究为 PES 类生物活性化合物提供了一种强大的新工具化合物，并深入了解了 PES 及其衍生物的工作机制。
PES (2-phenylethynesulfonamide, pifithrin-μ, PFTμ) is an electrophilic compound that exhibits anticancer properties, protects against chemotherapy-induced peripheral neuropathy in chemotherapy, and shows immunomodulatory, anti-inflammatory and anti-viral activities. PES generally shows higher cytotoxicity towards tumor cells than non-tumor cells. The mechanism of action of PES is unclear but may involve the covalent modification of proteins as PES has been found to be a covalent inhibitor of Hsp70. We developed a new PES derivative PESA with a terminal alkynyl group to perform click-reaction-assisted activity-based protein profiling (click-reaction ABPP) and used this to screen for cellular targets of PES. We found PES and its derivatives PES-Cl and PESA have comparable ability to undergo a Michael addition reaction with GSH and Hsp70, and showed similar cytotoxicity. By fluorescence imaging and proteomics studies we identified over 300 PESA-attached proteins in DOHH2 cells. Some proteins involved in cancer-related redox processes, such as peroxiredoxin 1 (PRDX1), showed higher frequency and abundance in mass spectrometry detection. Our results suggest that cytotoxicity of PES and its derivatives may be related to attack of protein thiols and cellular GSH resulting in breakdown of cellular redox homeostasis. This study provides a powerful new tool compound within the PES class of bioactive compounds and gives insight into the working mechanisms of PES and its derivatives.