Discovery of multi-target anti-gout agents from Eurycoma longifolia Jack through phenotypic screening and structural optimization
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-carboli...
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62645-6 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Zhijiao Zhang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-9de8f5f6b1534194b09aa1bf61df3abd |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-9de8f5f6b1534194b09aa1bf61df3abd2025-08-20T04:03:06ZengNature PortfolioNature Communications2041-17232025-08-0116111310.1038/s41467-025-62645-6Discovery of multi-target anti-gout agents from Eurycoma longifolia Jack through phenotypic screening and structural optimizationZhijiao Zhang0Xiaoyu Shi1Ting Wu2Zhuhan He3Ruipeng Liang4Wenjie Ye5Zhenkun Wu6Hui Liao7Fengxin Zheng8Qian Yang9Zean Zhao10Yongjun Chen11Zhen Gao12Shuo Wang13Mei Wang14Zhenqian Wang15Danhui Qi16Mingyu Yang17Shujing Xu18Youzhao Wang19Tong Zhao20Javier Egea21Xinyong Liu22Jianxin Pang23Fan Yi24Peng Zhan25State 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 UniversityState 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 UniversityNMPA 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 UniversityDepartment of Pharmacology; Shandong University School of MedicineState 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 UniversityNMPA 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 UniversityNMPA 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 UniversityNMPA 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 UniversityNMPA 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 UniversityState 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 UniversityNMPA 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 UniversityNMPA 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 UniversityState 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 UniversityState 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 UniversityState 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 UniversityState 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 UniversityState 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 UniversityState 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 UniversityState 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 UniversityDepartment of Pharmacology; Shandong University School of MedicineState 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 UniversityUnidad de Investigación, Hospital Santa Cristina, Instituto de Investigación Sanitaria Princesa (IIS-IP)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 UniversityNMPA 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 UniversityDepartment of Pharmacology; Shandong University School of MedicineState 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 UniversityAbstract 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.https://doi.org/10.1038/s41467-025-62645-6 |
| spellingShingle | 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 Discovery of multi-target anti-gout agents from Eurycoma longifolia Jack through phenotypic screening and structural optimization Nature Communications |
| title | Discovery of multi-target anti-gout agents from Eurycoma longifolia Jack through phenotypic screening and structural optimization |
| title_full | Discovery of multi-target anti-gout agents from Eurycoma longifolia Jack through phenotypic screening and structural optimization |
| title_fullStr | Discovery of multi-target anti-gout agents from Eurycoma longifolia Jack through phenotypic screening and structural optimization |
| title_full_unstemmed | Discovery of multi-target anti-gout agents from Eurycoma longifolia Jack through phenotypic screening and structural optimization |
| title_short | Discovery of multi-target anti-gout agents from Eurycoma longifolia Jack through phenotypic screening and structural optimization |
| title_sort | discovery of multi target anti gout agents from eurycoma longifolia jack through phenotypic screening and structural optimization |
| url | https://doi.org/10.1038/s41467-025-62645-6 |
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