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, Peng Zhan
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. Developing anti-gout medications that simultaneously reduce uric acid and exert anti-inflammatory effects is of interest for managing gout progression. Here, the authors employ a dual-target pharmacophore model to design derivatives of β-carboline-1-propionic acid and identify a drug candidate demonstrating potent uric acid-lowering activity in male hyperuricemia mouse models and mitigating NLRP3-mediated inflammation.