Fungal mycotoxin penisuloxazin A, a novel C-terminal Hsp90 inhibitor and characteristics of its analogues on Hsp90 function related to binding sites
Fungal mycotoxin penisuloxazin A, a novel C-terminal Hsp90 inhibitor and characteristics of its analogues on Hsp90 function related to binding sites
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真菌毒素penisuloxazin A，一种新型C端Hsp90抑制剂及其类似物对与结合位点相关的Hsp90功能的特性
DOI：
10.1016/j.bcp.2020.114218
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发表时间：
2020-12-01
影响因子：
5.8
通讯作者：
Li, Jing
中科院分区：
文献类型：
--
作者：
Dai, Jiajia;Zhu, Meilin;Li, Jing
Hsp90 是一个有前途的癌症治疗药物靶点。然而，由于广泛的蛋白质降解，毒性和中等效果是当前抑制剂的局限性。真菌毒素 Penisuloxazin A (PNSA) 属于一种新型表聚硫二酮哌嗪 (ETP)，具有罕见的 3H-螺[苯并呋喃-2,2'-哌嗪]环系统。 PNSA 通过二硫键与 CT-Hsp90 的半胱氨酸残基 C572/C598 结合，抑制 Hsp90 活性，导致体外和体内 HCT116 细胞凋亡和生长抑制。我们发现类似物 PEN-A 和 HDN-1 分别与 CT-Hsp90 α 的 C572/C597 和 C572 结合，结合模式与 PNSA 非常相似。这些ETP对ATPase活性、二聚化形成和对Hsp90客户蛋白的选择性表现出不同的影响，表明Hsp90的客户蛋白识别可以通过Hsp90的不同位点精确调控。我们的研究结果不仅为抗癌药物的开发提供了新的化学类型，而且有助于更好地了解 Hsp90 的生物学功能，以探索具有某些客户蛋白偏差的抑制剂。
Hsp90 is a promising drug target for cancer therapy. However, toxicity and moderate effect are limitations of current inhibitors owing to broad protein degradation. The fungal mycotoxin penisuloxazin A (PNSA) belongs to a new epipolythiodiketopiperazines (ETPs) possessing a rare 3H-spiro[benzofuran-2,2'-piperazine] ring system. PNSA bound to cysteine residues C572/C598 of CT-Hsp90 with disulfide bonds and inhibits Hsp90 activity, resulting in apoptosis and growth inhibition of HCT116 cells in vitro and in vivo. We identified that analogues PEN-A and HDN-1 bound to C572/C597 and C572 of CT-Hsp90 alpha respectively, with binding pattern very similar to PNSA. These ETPs exhibited different effects on ATPase activity, dimerization formation and selectivity on client protein of Hsp90, indicating client recognition of Hsp90 can be exactly regulated by different sites of Hsp90. Our findings not only offer new chemotypes for anticancer drug development, but also help to better understand biological function of Hsp90 for exploring inhibitor with some client protein bias.