Advances in the synthesis and engineering of conotoxins

IF 6 2区 医学 Q1 CHEMISTRY, MEDICINAL European Journal of Medicinal Chemistry Pub Date : 2024-11-10 DOI:10.1016/j.ejmech.2024.117038
Thao NT. Ho, Thanh Hoa Tran, Le Hoang Sinh, Richard J. Lewis
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Abstract

Conotoxins, isolated from the venom of carnivorous marine snails of the Conus genus, are disulfide-rich peptides and proteins with well-defined three-dimensional structures. Conotoxins’ ability to target a wide range of ion channels and receptors, including voltage- and ligand-gated ion channels, G protein-coupled receptors, monoamine transporters, and enzyme, at exquisite potency and selectivity make them valuable research and therapeutic tools. Despite their potentials, Conus venom peptides are present in limited quantities in nature and possess structural complexity that raises significant synthetic challenges for both chemical synthesis and recombinant expression. Here, we document recent advances in the expression and synthesis of conotoxins, particularly focusing on directed formation of disulfide bonds, chemical ligation techniques, and the integration of non-native functional groups. These advances can provide access to even the most complex conotoxins, accelerating conotoxin-based drug discovery and functional analysis, as well as opening new avenues for the development of drug candidates.

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芋螺毒素的合成和工程学研究进展
芋螺毒素从芋螺属食肉海螺的毒液中分离出来,是富含二硫化物的多肽和蛋白质,具有明确的三维结构。芋螺毒素能够靶向多种离子通道和受体,包括电压门控和配体门控离子通道、G 蛋白偶联受体、单胺转运体和酶,具有极高的效力和选择性,因此是非常有价值的研究和治疗工具。尽管柯纳斯毒液肽潜力巨大,但其在自然界中的数量有限,而且结构复杂,给化学合成和重组表达带来了巨大的合成挑战。在此,我们记录了表达和合成芋螺毒素的最新进展,特别是二硫键的定向形成、化学连接技术和非本地官能团的整合。即使是最复杂的芋螺毒素也可以通过这些技术获得,从而加速基于芋螺毒素的药物发现和功能分析,并为候选药物的开发开辟新途径。
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来源期刊
CiteScore
11.70
自引率
9.00%
发文量
863
审稿时长
29 days
期刊介绍: The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.
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