Discovery of multi-target anti-gout agents from Eurycoma longifolia Jack through phenotypic screening and structural optimization
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.
Authors
- Danhui Qi
- Zhijiao Zhang
- Fengxin Zheng
- Zhuhan He
- Fan Yi (ORCID: https://orcid.org/0000-0001-8634-9788)
- Zhenkun Wu (ORCID: https://orcid.org/0000-0001-6458-5659)
- Ting Wu (ORCID: https://orcid.org/0000-0002-2954-1279)
- Zean Zhao (ORCID: https://orcid.org/0000-0001-9589-9706)
- Zhenqian Wang (ORCID: https://orcid.org/0000-0002-1743-2227)
- Javier Egea (ORCID: https://orcid.org/0000-0003-4704-3019)
- Ruipeng Liang
- Youzhao Wang
- Xinyong Liu (ORCID: https://orcid.org/0000-0002-7302-2214)
- Jianxin Pang (ORCID: https://orcid.org/0000-0002-0053-2723)
- Peng Zhan (ORCID: https://orcid.org/0000-0002-9675-6026)
- Yongjun Chen (ORCID: https://orcid.org/0000-0001-5081-7762)
- Mei Wang (ORCID: https://orcid.org/0000-0002-7658-3797)
- Shuo Wang (ORCID: https://orcid.org/0000-0002-5151-6176)
- Shujing Xu (ORCID: https://orcid.org/0000-0002-7168-613X)
- Wenjie Ye (ORCID: https://orcid.org/0000-0001-6065-9905)
- Mingyu Yang (ORCID: https://orcid.org/0000-0003-0986-3825)
- Hui Liao (ORCID: https://orcid.org/0000-0002-1464-3301)
- Zhen Gao (ORCID: https://orcid.org/0000-0002-6892-0706)
- Xiaoyu Shi (ORCID: https://orcid.org/0009-0002-5893-591X)
- Qian Yang (ORCID: https://orcid.org/0009-0002-9562-8361)
- Tong Zhao (ORCID: https://orcid.org/0009-0008-0193-0812)
Institutions
- Shandong University of Traditional Chinese Medicine (CN)
- Shandong University (CN)
- Guangdong Pharmaceutical University (CN)
- University of Jinan (CN)
- Hospital Universitario Santa Cristina (ES)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-11
- DOI
- https://doi.org/10.1038/s41467-025-62645-6
- Citations
- 6
- Primary Topic
- Phytochemical compounds biological activities
- Type
- article
- Field-Weighted Citation Impact
- 4.84
Funders
- National Natural Science Foundation of China