| 张自轩,梁家珍,江涛,等.基于二聚化修饰的α-芋螺毒素Mr1.1的设计、合成及活性评价[J].中国海洋药物,2025,(3):-. |
| 基于二聚化修饰的α-芋螺毒素Mr1.1的设计、合成及活性评价 |
| Design, synthesis and activity evaluation of α-conotoxin Mr1.1 based on dimerization modification |
| 投稿时间：2024-01-22 修订日期：2024-03-15 |
| DOI： |
| 中文关键词: 芋螺毒素 二聚化 α9α10 nAChR Mr1.1 |
| English Keywords:conotoxin dimerization α9α10 nAChR Mr1.1 |
| Fund Project: |
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| 中文摘要: |
| 目的 本研究旨在通过点击化学反应(Click反应)合成Mr1.1的二聚体,以提升其对神经病理疼痛治疗靶标α9α10烟碱型乙酰胆碱受体(α9α10 nAChRs)抑制活性,为新型镇痛药物的开发提供支持。方法 通过多肽固相合成技术,合成了叠氮化的Mr1.1,并合成了一个含有两个炔基官能团的linker,进而通过click反应偶联形成Mr1.1二聚体。通过显微注射技术,在非洲爪蟾的卵母细胞中表达了α9α10 nAChRs,通过电生理学技术评估了Mr1.1二聚体对该受体的抑制活性。结果 Mr1.1二聚体在电生理学水平上显示出远高于野生型Mr1.1的活性,其对α9α10 nAChRs的抑制活性提高了约46倍。结论 本研究合成的Mr1.1的二聚体显著提高了其对α9α10 nAChR的抑制活性,使其具有发展成为新型非成瘾性镇痛药物的潜在价值,且这一策略为合理药物设计提供了新的思路。 |
| English Summary: |
| Objective The dimer Mr1.1 was synthesized via an in-solution click reaction to enhance its potency at human α9α10 nicotinic acetylcholine receptors (α9α10 nAChRs), a therapeutic target associated with neurophathic pain, providing support for the development of new analgesic drugs. Methods The azide Mr1.1 was synthesized by solid-phase peptide synthesis and the linker containing two alkynyl groups was also obtained, then dimer Mr1.1 was synthesized between the azide and alkynyl groups through a click reaction. Through microinjection techniques, the expression of α9α10 nAChR was achieved in Xenopus laevis oocytes, and the biological activity of the Mr1.1 dimer on this receptor was assessed using electrophysiological methods. Results The results indicated that the dimer Mr1.1 exhibits significantly higher activity compared to the wild-type Mr1.1. Its inhibitory activity against α9α10 nAChR has been increased by approximately 46-fold. Conclusion The dimer Mr1.1 significantly improved potency at α9α10 nAChR over Mr1.1, making it have the potential as a new non-addictive analgesic drug, and this strategy also provides a new method for rational drug design. |
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