School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
Chemical Biology Research Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Signal Transduct Target Ther. 2023 Feb 3;8(1):51. doi: 10.1038/s41392-022-01231-4.
As a terpenoids natural product isolated from the plant Thunder God Vine, Celastrol is widely studied for its pharmacological activities, including anti-tumor activities. The clinical application of Celastrol is strictly limited due to its severe side effects, whereas previously revealed targets and mechanism of Celastrol seldom reduce its in vivo toxicity via structural optimization. Target identification has a far-reaching influence on the development of innovative drugs, and omics data has been widely used for unbiased target prediction. However, it is difficult to enrich target of specific phenotype from thousands of genes or proteins, especially for natural products with broad promising activities. Here, we developed a text-mining-based web-server tool to enrich targets from omics data of inquired compounds. Then peroxiredoxin 1 (PRDX1) was identified as the ROS-manipulating target protein of Celastrol in colorectal cancer. Our solved high-resolution crystal structure revealed the unique covalent binding mode of Celastrol with PRDX1. New derivative compound 19-048 with improved potency against PRDX1 and selectivity towards PRDX2~PRDX6 were synthesized based on crystal structure analysis. Both Celastrol and 19-048 effectively suppressed the proliferation of colorectal cancer cells. The anti-tumor efficacy of Celastrol and 19-048 was significantly diminished on xenograft nude mice bearing PRDX1 knock-down colorectal cancer cells. Several downstream genes of p53 signaling pathway were dramatically up-regulated with Celastrol or 19-048 treatment. Our findings reveal that the side effects of Celastrol could be reduced via structural modification, and PRDX1 inhibition is promising for the treatment of colorectal cancer.
从雷公藤植物中分离得到的萜类天然产物，Celastrol 因其药理学活性而被广泛研究，包括抗肿瘤活性。由于 Celastrol 的严重副作用，其临床应用受到严格限制，而先前揭示的 Celastrol 靶点和机制很少通过结构优化来降低其体内毒性。靶标鉴定对创新药物的发展具有深远的影响，组学数据已被广泛用于无偏靶标预测。然而，从数千个基因或蛋白质中富集特定表型的靶标非常困难，特别是对于具有广泛应用前景的天然产物。在这里，我们开发了一种基于文本挖掘的网络服务器工具，从所研究化合物的组学数据中富集靶标。然后，过氧化物酶 1（PRDX1）被鉴定为 Celastrol 在结直肠癌中的 ROS 调控靶蛋白。我们解决的高分辨率晶体结构揭示了 Celastrol 与 PRDX1 的独特共价结合模式。基于晶体结构分析，合成了对 PRDX1 具有更好活性和对 PRDX2~PRDX6 更高选择性的新型衍生物化合物 19-048。Celastrol 和 19-048 均能有效抑制结直肠癌细胞的增殖。在异种移植裸鼠结直肠癌细胞中敲低 PRDX1 后，Celastrol 和 19-048 的抗肿瘤疗效明显减弱。p53 信号通路的几个下游基因在 Celastrol 或 19-048 处理后显著上调。我们的研究结果表明，通过结构修饰可以降低 Celastrol 的副作用，PRDX1 抑制有望成为治疗结直肠癌的一种方法。
