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  3. Discovery of cyanidin-3-O-galactoside as a novel CNT2 inhibitor for the treatment of hyperuricemia

Discovery of cyanidin-3-O-galactoside as a novel CNT2 inhibitor for the treatment of hyperuricemia

  • Bioorg Chem. 2025 Jan:154:108108. doi: 10.1016/j.bioorg.2024.108108.
Fengxin Zheng 1,  Jiale Ke 1,  Shiqin Lin 2,  Wenjie Ye 1,  Zhenkun Wu 1,  Yuexin Xu 1,  Suiqing Mai 2,  Yishuang Chen 2,  Zitao Guo 1,  Huazhong Hu 2,  Shuqin Zhang 2,  Jianxin Pang 3,  Qun Zhang 4,  Zean Zhao 5
Affiliations

Affiliations

  • 1 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 510515, China.
  • 2 Good Clinical Practice Development, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China.
  • 3 Good Clinical Practice Development, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital, Southern Medical University, Guangzhou, 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 510515, China. Electronic address: pjx@smu.edu.cn.
  • 4 Good Clinical Practice Development, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China. Electronic address: zhangqun123456@126.com.
  • 5 Good Clinical Practice Development, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China. Electronic address: zhaozean666@smu.edu.cn.
PMID: 39753042 DOI: 10.1016/j.bioorg.2024.108108
Abstract

Inhibition of human concentrative nucleoside transporter 2 (CNT2) could suppress increases in serum urate levels derived from dietary purines. However, the structural basis for substrate recognition of CNT2 is still unknown and only a few inhibitors have been reported. In this study, a homology model of CNT2 was constructed and residues T315, E316, N426, N491, E492, F536 and N538 were identified as binding sites for adenosine through site-directed mutagenesis and a 3H-adenosine uptake assay. To explore potential CNT2 inhibitors, a database containing 4704 Saccharides and glycosides was constructed, followed by high-throughput virtual screening. The top 20 compounds with the highest docking scores were then evaluated their in vitro activity. Among them, cyanidin-3-O-galactoside (Cy3Gal) demonstrated the most potent inhibitory activity against CNT2, exhibiting an IC50 value of 9.40 μM. Docking analysis revealed that residues M314, T315, T347, N422, F536 and S541 contributed to a strong binding affinity with Cy3Gal. In addition, Cy3Gal exhibited minimal inhibitory effects on CNT3 and equilibrative Nucleoside Transporters (ENTs) in vitro. At doses of 5-20 mg/kg, Cy3Gal effectively reduced serum and urine levels of uric acid and adenosine in vivo. The CCK-8 assay revealed that Cy3Gal displayed minimal cytotoxicity to mTEC and hIEC cells at a concentration of 100 μM. The serum CR and BUN levels indicate that Cy3Gal does not exhibit any apparent renal toxicity compared to lesinurad and allopurinol. HE examination showed no noticeable pathological changes in the kidneys or colons after treatment with Cy3Gal. In summary, Cy3Gal could be a CNT2 inhibitor with favorable drugability for the treatment of hyperuricemia.

Keywords

Anthocyanin; Concentrative nucleoside transporter 2; Cyanidin-3-O-galactoside; Gout; Hyperuricemia.

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