Engineering stable peptide toxins by means of backbone cyclization:: Stabilization of the α-conotoxin MII
Engineering stable peptide toxins by means of backbone cyclization:: Stabilization of the α-conotoxin MII
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DOI：
10.1073/pnas.0504613102
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发表时间：
2005-09-27
影响因子：
11.1
通讯作者：
Craik, DJ
中科院分区：
文献类型：
--
作者：
Clark, RJ;Fischer, H;Craik, DJ
芋螺毒素（CTX），以其精致的特异性和效力，最近创造了许多令人兴奋的药物线索。然而，像大多数肽一样，它们的有益活性可能会被体内蛋白水解的易感性破坏。通过使用一系列接头环化α-CTX MII，我们已经改造了保留其全部活性但对蛋白水解降解具有极大改善的抗性的肽。环状MII类似物含有7个残基的接头连接的N和C末端的活性和选择性的天然肽的天然和重组神经元烟碱乙酰胆碱受体亚型存在于牛嗜铬细胞和Xerl卵母细胞中表达，分别。此外，其对针对特定蛋白酶和人血浆中的蛋白水解的抗性显著提高。更一般地说，据我们所知，这是第一份关于富含二硫化物的毒素环化的报告。环化策略代表了一种稳定生物活性肽同时保持其全部效力的方法，并且应该促进基于肽的药物在人类医学中的应用。
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.