Marked increase in membranolytic selectivity of novel cyclic tachyplesins constrained with an antiparallel two-beta strand cystine knot framework.
Marked increase in membranolytic selectivity of novel cyclic tachyplesins constrained with an antiparallel two-beta strand cystine knot framework.
复制标题
DOI：
10.1006/bbrc.1999.2035
复制
发表时间：
2000-01
影响因子：
3.1
通讯作者：
J. Tam;Y. A. Lu;J. Yang
中科院分区：
文献类型：
--
作者：
J. Tam;Y. A. Lu;J. Yang
我们已经开发了一个高度限制的18个残基的环肽模板的基础上的抗菌肽tachyplesin-1，其特征是一个端到端的肽骨架和一个胱氨酸结样基序与三个均匀间隔的二硫键交叉支撑的反平行β链和近似的两亲性的"β瓦"样结构。制备六种β-tile类似物以将不同的拓扑模式与膜溶解特异性相关联。它们的构象和抗菌和溶血活性进行了比较，与tachyplesin-1和最近发现的恒河猴theta防御素（RTD），其中包含类似的β-tile结构元件。β肽和RTD保留了广谱抗微生物活性。在一般情况下，他们比tachiplesin-1在10个测试的生物体，但其活性增加高盐（100 mM NaCl），而不是在低盐条件下。β肽对人红细胞高度无毒，EC（25）范围为600至4000 μ M。总的来说，我们的研究结果表明，设计一个高度刚性的肽模板是有用的进一步类似物的研究，从细胞毒性分离的抗菌活性，这将有助于发现肽抗生素的临床应用。
We have developed a highly constrained 18-residue cyclic peptide template based on the antimicrobial peptide tachyplesin-1 that features an end-to-end peptide backbone and a cystine knot-like motif with three evenly spaced disulfide bonds to cross-brace the antiparallel beta-strands and to approximate an amphiphatic "beta-tile"-like structure. Six beta-tile analogs were prepared to correlate different topological patterns with membranolytic specificity. Their conformations and antimicrobial and hemolytic activities were compared with tachyplesin-1 and the recently discovered Rhesus monkey theta defensin (RTD) which contains similar beta-tile structural elements. The beta-tile peptides and RTD retained broad spectrum antimicrobial activities. In general, they were less active than tachyplesin-1 in 10 tested organisms but their activity increased under high-salt (100 mM NaCl) rather than in low-salt conditions. The beta-tile peptides are highly nontoxic to human erythrocytes with EC(25) ranging from 600 to 4000 microM. Collectively, our results show that the design of a highly rigid peptide template is useful for further analog study to dissociate antimicrobial activity from cytotoxicity which would be helpful in discovering clinical applications for peptide antibiotics.