| 陈晓乐#,张平#,范秀梅,等.靶向去甲肾上腺素转运体芋螺毒素χ-MrIAEM的结构优化与构效关系研究[J].中国海洋药物,2026,(6):-. |
| 靶向去甲肾上腺素转运体芋螺毒素χ-MrIAEM的结构优化与构效关系研究 |
| Study on structural optimization and structure-activity relationship of conotoxin χ-MrIAEM targeting norepinephrine transporter |
| 投稿时间：2025-10-16 修订日期：2025-11-04 |
| DOI： |
| 中文关键词: 芋螺毒素 去甲肾上腺素转运体 血清稳定性 |
| English Keywords:conotoxin norepinephrine transporter serum stability |
| Fund Project: |
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| 中文摘要: |
| 目的 本研究通过分析χ-MrIAEM与去甲肾上腺素转运体（NET）复合物晶体结构，优化其结构以提升活性与稳定性，探索构效关系，筛选具有镇痛潜力的苗头分子。方法 采用多肽固相合成法构建12条χ-MrIAEM定点突变类似物，通过放射性摄取实验测定其对NET的抑制活性，利用人血清稳定性实验评估代谢稳定性，并结合分子对接分析关键作用位点。结果 多数突变体活性下降，但C5Pen和C14Pen在400 nM下仍保有抑制活性，且在人血清中的稳定性均提高，其中C14Pen的半衰期延长至5 h，提升更为显著。结论 本研究合成的C14Pen在保持高活性的同时具备良好的代谢稳定性，具备开发为非阿片类镇痛药物的潜力为后续体内药效与成药性研究提供基础，且这一策略为合理药物设计提供了新的思路。 |
| English Summary: |
| Objective This study aimed to optimize the structure of χ-MrIAEM for improved potency and stability by analyzing the crystal structure of the χ-MrIAEM–norepinephrine transporter (NET) complex, to explore structure–activity relationships and to identify analgesic hit molecules. Methods Twelve site-directed analogues of χ-MrIAEM were prepared by solid-phase peptide synthesis. Their inhibitory activity against NET was quantified with a radiolabeled uptake assay. Metabolic stability was assessed in human serum, and key interaction residues were elucidated by molecular docking. Results Although most mutants showed reduced activity, C5Pen and C14Pen retained inhibitory potency at 400 nM and demonstrated improved stability in human serum, with C14Pen exhibiting a more pronounced enhancement, extending its half-life to 5 h. Conclusion C14Pen maintains high potency while exhibiting excellent metabolic stability, making it a promising non-opioid analgesic lead. The work lays the foundation for subsequent in vivo efficacy and developability studies, and offers a new rationale for structure-based peptide drug design. |
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