| 卢璐,刘国平,于日磊.源于织锦芋螺转录组的新型芋螺毒素的合成与活性研究[J].中国海洋药物,2026,(2):-. |
| 源于织锦芋螺转录组的新型芋螺毒素的合成与活性研究 |
| Synthesis and Activity Evaluation of Novel Conotoxin Sequences derived from the Transcriptome of Conus textile |
| 投稿时间：2025-02-18 修订日期：2025-04-10 |
| DOI： |
| 中文关键词: 芋螺毒素 α7烟碱型乙酰胆碱受体 分子动力学模拟 固相合成 |
| English Keywords:conotoxins α7 nicotinic acetylcholine receptors molecular dynamics simulations solid-phase synthesis |
| Fund Project: |
|
| 摘要点击次数: 90 |
| 全文下载次数: 0 |
| 中文摘要: |
| 目的 本研究旨在通过化学合成方法制备四条从织锦芋螺毒液中鉴定获得的、具有特征性二硫键骨架结构的新型芋螺毒素（TxI1、TxV1、TxXIV1和TxXXIV1），通过系统活性筛选与构效关系研究，为开发高效的靶向hα7 nAChRs多肽抑制剂提供理论依据和候选分子。方法 采用Fmoc固相合成技术制备目标多肽，并通过双电极电压钳技术在非洲爪蟾卵母细胞中测定其对hα7 nAChRs的抑制活性。随后，使用AlphaFold3预测多肽与hα7 nAChRs复合物的三维结构，并进行分子动力学模拟分析结合模式。结果 成功鉴定出两条对hα7 nAChRs具有显著抑制活性的芋螺毒素TxV1和TxXXIV1，其中TxXXIV1在10 μM浓度下达到70%的抑制率。结合模式分析显示，TxXXIV1通过与受体形成氢键和π-π堆积，有效抑制受体功能。结论 本研究通过结合多肽合成、活性评估与分子动力学模拟，成功得到两条对hα7 nAChRs有抑制活性的新型芋螺毒素，为基于多肽的hα7 nAChRs抑制剂药物开发提供了重要的理论和实验支持。 |
| English Summary: |
| Objective This study aims to chemically synthesize four novel conotoxins (TxI1, TxV1, TxXIV1, and TxXXIV1) with characteristic disulfide bond frameworks identified from the venom of Conus textile. Through systematic activity screening and structure-activity relationship studies, this research aims to provide a theoretical foundation and candidate molecules for the development of highly effective peptide inhibitors targeting hα7 nAChRs. Methods The target peptides were synthesized using Fmoc solid-phase peptide synthesis. Their inhibitory activity against hα7 nAChRs was assessed using two-electrode voltage-clamp techniques in Xenopus laevis oocytes. Subsequently, the three-dimensional structure of the peptides in complex with hα7 nAChRs was predicted using AlphaFold3, followed by molecular dynamics simulations to analyze the binding mode. Results Two conotoxins, TxV1 and TxXXIV1, demonstrated significant inhibitory activity against hα7 nAChRs. Notably, TxXXIV1 achieved a 70% inhibition rate at a concentration of 10 μM. Binding mode analysis revealed that TxXXIV1 effectively inhibits receptor function through the formation of hydrogen bonds and π-π stacking interactions with the receptor. Conclusion This study successfully identified two novel conotoxins with inhibitory activity against hα7 nAChRs by combining peptide synthesis, activity evaluation, and molecular dynamics simulations. These findings provide important theoretical and experimental support for the development of peptide-based hα7 nAChRs inhibitors. |
| 查看/发表评论 下载PDF阅读器 |
|
| 关闭 |