Discovery of multi-target anti-gout agents from Eurycoma longifolia Jack through phenotypic screening and structural optimization

IF 15.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2025-08-12 DOI:10.1038/s41467-025-62645-6

Zhijiao Zhang, Xiaoyu Shi, Ting Wu, Zhuhan He, Ruipeng Liang, Wenjie Ye, Zhenkun Wu, Hui Liao, Fengxin Zheng, Qian Yang, Zean Zhao, Yongjun Chen, Zhen Gao, Shuo Wang, Mei Wang, Zhenqian Wang, Danhui Qi, Mingyu Yang, Shujing Xu, Youzhao Wang, Tong Zhao, Javier Egea, Xinyong Liu, Jianxin Pang, Fan Yi, Peng Zhan

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Abstract

Developing anti-gout medications that simultaneously reduce uric acid and exert anti-inflammatory effects represents a critical breakthrough for managing gout progression. Natural products with polypharmacological properties offer promising leads for drug discovery. In this study, β-carboline-1-propionic acid, a bioactive constituent of Eurycoma longifolia Jack, served as the starting point for drug design. Guided by a dual-target pharmacophore model, we design and synthesize 64 derivatives. Through systematic screening, 32 emerges as a drug candidate, demonstrating potent uric acid-lowering activity in male hyperuricemia mouse models (efficacy comparable to febuxostat and superior to lesinurad and benzbromarone) by inhibiting key urate transporters. In a male rat model of acute gouty arthritis, 32 mitigates NOD-like receptor protein 3 inflammasome-mediated inflammation. Notably, 32 exhibits enhanced safety compared to control drugs. This study exemplifies a natural product-inspired, dual-mechanism drug discovery approach, showcasing the potential of a rational polypharmacology and thus offering therapeutic opportunities for gout management.

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通过表型筛选和结构优化发现长叶Eurycoma longifolia Jack多靶点抗痛风药物

开发抗痛风药物，同时减少尿酸和发挥抗炎作用代表了一个关键的突破管理痛风的进展。具有多种药理特性的天然产物为药物发现提供了有希望的线索。本研究以长叶Eurycoma longifolia Jack的生物活性成分β-carboline-1-丙酸作为药物设计的起点。在双靶点药效团模型的指导下，我们设计并合成了64种衍生物。通过系统筛选，32成为候选药物，通过抑制关键的尿酸转运蛋白，在雄性高尿酸血症小鼠模型中显示出有效的降尿酸活性（效果与非布司他相当，优于莱西努拉德和苯溴马龙）。在急性痛风性关节炎的雄性大鼠模型中，32减轻nod样受体蛋白3炎症小体介导的炎症。值得注意的是，与对照药物相比，32显示出更高的安全性。本研究举例说明了一种天然产品启发，双机制药物发现方法，展示了合理的多药理学的潜力，从而为痛风管理提供了治疗机会。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.