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

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 () and Peng Zhan ()
Additional contact information
Zhijiao Zhang: Shandong University
Xiaoyu Shi: Shandong University
Ting Wu: Southern Medical University
Zhuhan He: Department of Pharmacology; Shandong University School of Medicine
Ruipeng Liang: Shandong University
Wenjie Ye: Southern Medical University
Zhenkun Wu: Southern Medical University
Hui Liao: Southern Medical University
Fengxin Zheng: Southern Medical University
Qian Yang: Shandong University
Zean Zhao: Southern Medical University
Yongjun Chen: Southern Medical University
Zhen Gao: Shandong University
Shuo Wang: Shandong University
Mei Wang: Shandong University
Zhenqian Wang: Shandong University
Danhui Qi: Shandong University
Mingyu Yang: Shandong University
Shujing Xu: Shandong University
Youzhao Wang: Department of Pharmacology; Shandong University School of Medicine
Tong Zhao: Shandong University
Javier Egea: Instituto de Investigación Sanitaria Princesa (IIS-IP)
Xinyong Liu: Shandong University
Jianxin Pang: Southern Medical University
Fan Yi: Department of Pharmacology; Shandong University School of Medicine
Peng Zhan: Shandong University

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62645-6

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