Zhang Zhijiao, Shi Xiaoyu, Wu Ting, He Zhuhan, Liang Ruipeng, Ye Wenjie, Wu Zhenkun, Liao Hui, Zheng Fengxin, Yang Qian, Zhao Zean, Chen Yongjun, Gao Zhen, Wang Shuo, Wang Mei, Wang Zhenqian, Qi Danhui, Yang Mingyu, Xu Shujing, Wang Youzhao, Zhao Tong, Egea Javier, Liu Xinyong, Pang Jianxin, Yi Fan, Zhan Peng
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P. R. China.
NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, P. R. China.
Nat Commun. 2025 Aug 12;16(1):7430. doi: 10.1038/s41467-025-62645-6.
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.
开发同时降低尿酸并发挥抗炎作用的抗痛风药物是控制痛风进展的关键突破。具有多种药理特性的天然产物为药物发现提供了有前景的线索。在本研究中，长叶淫羊藿的生物活性成分β-咔啉-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种衍生物成为候选药物，通过抑制关键尿酸转运蛋白，在雄性高尿酸血症小鼠模型中显示出强大的降尿酸活性（疗效与非布司他相当，优于雷西纳德和苯溴马隆）。在雄性急性痛风性关节炎大鼠模型中，32种衍生物减轻了NOD样受体蛋白3炎性小体介导的炎症。值得注意的是，与对照药物相比，32种衍生物表现出更高的安全性。本研究例证了一种受天然产物启发的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。
