Toggling Preassembly with Single-Site Mutation Switches the Cytotoxic Mechanism of Cationic Amphipathic Peptides
Toggling Preassembly with Single-Site Mutation Switches the Cytotoxic Mechanism of Cationic Amphipathic Peptides
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通过单位点突变切换预组装可切换阳离子两亲肽的细胞毒性机制
DOI：
10.1021/acs.jmedchem.9b01458
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发表时间：
2020-02-13
影响因子：
7.3
通讯作者：
Fei, Hao
中科院分区：
文献类型：
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作者：
Chen, Xiaolong;Ji, Shuangshuang;Fei, Hao
对膜活性多肽活性的精确调控是促进其应用翻译的研究前沿。清楚地了解多肽的物理化学性质如何决定其作用模式(MOA)将有助于这一过程。在这里，基于阴离子谷氨酸残基的扫描应用于自组装的富含赖氨酸的阳离子两亲性多肽(CAP)KL1的疏水表面。从亮氨酸到谷氨酸的单点突变极大地改变了所有突变体的MOA，从膜溶解变为非溶解。一个不能在细胞外阴离子下自组装的诱导凋亡突变体L2E在两亲性环境中表现出与KL1不同的构象转化过程。进一步调整总正电荷允许调节细胞毒效力，而不影响由缺乏预组装形成所确定的MOA。与KL1相比，非膜溶血肽的溶血毒性显著降低，安全性指数增加。因此，这项工作为改善抗癌活性和安全性的CAPS提供了新的见解和综合的理论基础。
Precise regulation of membrane-active peptide activity is a frontier of research to facilitate its applicational translation. A clear understanding of how a peptide's physicochemical properties determine its mode of action (MOA) will aid the process. Herein, anionic glutamate residue-based scanning was applied to the hydrophobic surface of a self-assembling lysine-rich cationic amphipathic peptide (CAP) KL1. Single-site mutations from leucine to glutamate dramatically changed the MOA of all mutants from membranolytic to nonlytic. An apoptosis-inducing mutant L2E unable to self-assemble under extracellular anions exhibited a different conformational transformation process in the amphiphilic environment than KL1. Further adjustment of the overall positive charge allowed regulation of cytotoxic potency without affecting the MOA determined by the lack of preassembly formation. Compared with KL1, hemolytic toxicities of nonmembranolytic peptides were greatly reduced, with safety indices increased. This work thus provided novel insights into and integrated rationales on the improvement of CAPs for both anticancer activity and safety profile.