2. Academic Validation
  3. 5-O-Methylvisammioside, a novel inhibitor of CNT2, improves hyperuricemia by inhibiting intestinal purine nucleoside absorption with a safe profile

5-O-Methylvisammioside, a novel inhibitor of CNT2, improves hyperuricemia by inhibiting intestinal purine nucleoside absorption with a safe profile

  • Biochem Pharmacol. 2025 Aug 13;242(Pt 1):117236. doi: 10.1016/j.bcp.2025.117236.
Suiqing Mai 1,  Jiale Ke 2,  Shiqin Lin 1,  Rongrong Huang 1,  Fengxin Zheng 2,  He Jiao 1,  Hong Wang 1,  Shuqin Zhang 1,  Mengying Mao 1,  Qiuping Li 1,  Zean Zhao 3,  Jianxin Pang 4,  Qun Zhang 5
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China.
  • 2 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.
  • 3 Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China. Electronic address: [email protected].
  • 4 Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, 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: [email protected].
  • 5 Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China. Electronic address: [email protected].
PMID: 40816627 DOI: 10.1016/j.bcp.2025.117236
Abstract

A high-purine diet is an important factor in the development of hyperuricemia (HUA), in which the intestinal tract is the main site of dietary purine absorption. Inhibition of intestinal concentrative nucleoside transporter 2 (CNT2) can inhibit dietary purine-induced elevation of serum uric acid (sUA) levels. However, there is a lack of research on CNT2 inhibitors for the treatment of HUA. By using high throughput virtual screening from an in-house natural product database, the natural active component 5-methylvisammioside (MeV) in Saposhnikovia divaricata (Turcz.) Schischk was predicted to be an effective CNT2 inhibitor with the highest docking score. In vitro,MeV showed the strongest inhibitory activity against CNT2, with IC50 value of 11.22 ± 2.18 μM. Moreover, MeV showed little or almost no inhibitory effect on other Nucleoside Transporters CNT3 and equilibrative Nucleoside Transporters (ENTs), as well as on uric acid (UA) transporter-related targets. In vivo, MeV significantly reduced sUA, inhibited adenosine uptake, and had an ameliorative effect on pathological changes in the liver, kidney, and intestinal tract. Moreover, MeV improved serum and intestinal indices related to inflammation and oxidative stress in mice, reduced intestinal permeability. Through our further study, we found that MeV inhibited the activation of Reactive Oxygen Species (ROS) and NF-κB P65, reduced the production of the NOD-like Receptor protein 3 (NLRP3) inflammasome, and improved intestinal injury in a high UAenvironment. The study suggests that MeV is a potent CNT2 inhibitor for the treatment ofHUA and also protects intestinal function by inhibiting the ROS/NF-κB/NLRP3 pathway.

Keywords

CNT2; Dietary purine nucleosides; HUA; Intestinal Injury; MeV.

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