MacRaild Christopher A, Illesinghe Jayamini, van Lierop Bianca J, Townsend Amanda L, Chebib Mary, Livett Bruce G, Robinson Andrea J, Norton Raymond S
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3050, Victoria, Australia.
J Med Chem. 2009 Feb 12;52(3):755-62. doi: 10.1021/jm8011504.
The alpha-conotoxins are potent and selective antagonists of nicotinic acetylcholine receptors (nAChR). Exploitation of these and other peptides in research and clinical settings has been hampered by the lability of the disulfide bridges that are essential for toxin structure and activity. One solution to this problem is replacement of cystine bridges with nonreducible dicarba linkages. We explore this approach by determining the solution structure and functional characteristics of a dicarba analogue of the alpha-conotoxin alpha-ImI, (2,8)-dicarba-(3,12)-cystino alpha-ImI. The structure of the dicarba analogue was similar to that of native alpha-ImI, with differences attributable to the different covalent geometry of the disulfide and dicarba bridges. Dicarba-alpha-ImI maintained inhibitory activity of nAChR comparable to that of native alpha-ImI in two in vitro assays. These findings confirm the potential of the dicarba linkage to improve stability while maintaining alpha-conotoxin function.
α-芋螺毒素是烟碱型乙酰胆碱受体（nAChR）的强效和选择性拮抗剂。这些肽和其他肽在研究和临床环境中的应用受到二硫键不稳定性的阻碍，而二硫键对于毒素的结构和活性至关重要。解决这一问题的一种方法是用不可还原的二碳键取代胱氨酸桥。我们通过确定α-芋螺毒素α-ImI的二碳类似物（2,8）-二碳-（3,12）-胱氨酸-α-ImI的溶液结构和功能特性来探索这种方法。二碳类似物的结构与天然α-ImI相似，差异归因于二硫键和二碳键不同的共价几何结构。在两项体外试验中，二碳-α-ImI对nAChR的抑制活性与天然α-ImI相当。这些发现证实了二碳键在提高稳定性同时保持α-芋螺毒素功能方面的潜力。
