Structural Permutation of Potent Cytotoxin, Polytheonamide B : Discovery of Cytotoxic Peptide with Altered Activity
Structural Permutation of Potent Cytotoxin, Polytheonamide B : Discovery of Cytotoxic Peptide with Altered Activity
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强效细胞毒素聚神酰胺 B 的结构排列：发现具有改变活性的细胞毒性肽
DOI：
10.1021/ml300264c
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发表时间：
2013
影响因子：
4.2
通讯作者：
Masayuki Inoue
中科院分区：
文献类型：
--
作者：
Hiroaki Itoh;Masayuki Inoue
聚茶酰胺B（1）是一种具有α，β-交替的48个氨基酸序列的离子通道形成天然肽，是一种非常有效的细胞毒素。我们最近设计并合成了一个简化的丹磺酰化聚茶酰胺模拟物2，其中6个氨基酸残基是由1修饰的，并证明2模拟了1的功能。在这里，我们报告了一个全面的构效关系研究的亚结构2。开发了一种统一的合成策略，用于高度自动化合成27至39个氨基酸残基的13个肽序列，并且发现人工37-mer肽6对P388小鼠白血病细胞的毒性显著高于其他12种化合物（IC 50 = 3.7 nM）。用脂质体和P388细胞对6进行的离子交换活性实验均表明6不具有离子通道活性，这强烈表明6通过与1和2不同的作用模式发挥其强有力的细胞毒性。
Polytheonamide B (1) is an ion-channel forming natural peptide with ad,l-alternating 48 amino acid sequence, which is an exceedingly potent cytotoxin. We recently designed and synthesized a simplified dansylated polytheonamide mimic2, in which six amino acid residues were modified from1, and demonstrated that2emulated the functions of1. Here we report a comprehensive structure–activity relationship study of substructures of2. A unified synthetic strategy was developed for highly automated syntheses of 13 peptide sequences of 27 to 39 amino acid residues, and the artificial 37-mer peptide6was discovered to be significantly more toxic than the other 12 compounds toward P388 mouse leukemia cells (IC50= 3.7 nM). Ion exchange activity experiments of6using the liposome and P388 cells both demonstrated that6did not possess ion-channel activity, strongly suggesting that6exerted its potent cytoxicity through a distinct mode of action from1and2.