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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Engineering stable peptide toxins by means of backbone cyclization: Stabilization of the alpha-conotoxin MII
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Engineering stable peptide toxins by means of backbone cyclization: Stabilization of the alpha-conotoxin MII

机译：通过骨架环化工程稳定肽毒素：稳定α-芋螺毒素MII

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摘要

Conotoxins (CTXs), with their exquisite specificity and potency, have recently created much excitement as drug leads. However, like most peptides, their beneficial activities may potentially be undermined by susceptibility to proteolysis in vivo. By cyclizing the alpha-CTX MII by using a range of linkers, we have engineered peptides that preserve their full activity but have greatly improved resistance to proteolytic degradation. The cyclic MII analogue containing a seven-residue linker joining the N and C termini was as active and selective as the native peptide for native and recombinant neuronal nicotinic acetylcholine receptor subtypes present in bovine chromaffin cells and expressed in Xerl oocytes, respectively. Furthermore, its resistance to proteolysis against a specific protease and in human plasma was significantly improved. More generally, to our knowledge, this report is the first on the cyclization of disulfide-rich toxins. Cyclization strategies represent an approach for stabilizing bioactive peptides while keeping their full potencies and should boost applications of peptide-based drugs in human medicine.
机译：芋螺毒素（CTX）具有出色的特异性和效力，最近作为药物线索引起了极大的兴趣。但是，像大多数肽一样，它们的有益活性可能会因体内对蛋白水解的敏感性而受到破坏。通过使用一系列接头使α-CTXMII环化，我们设计了能够保留其全部活性但大大提高了对蛋白水解降解抗性的肽。含有连接N和C末端的7个残基的环状MII类似物，与存在于牛嗜铬细胞中并在Xerl卵母细胞中表达的天然和重组神经元烟碱型乙酰胆碱受体亚型的天然肽一样，具有活性和选择性。此外，其对蛋白水解蛋白对特定蛋白酶和在人血浆中的抗性显着提高。更广泛地说，据我们所知，该报告是有关富含二硫键的毒素环化的首份报告。环化策略代表了一种稳定生物活性肽并同时保持其全部效力的方法，并且应促进基于肽的药物在人类医学中的应用。

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