Membranolytic selectivity of cystine-stabilized cyclic protegrins.
Membranolytic selectivity of cystine-stabilized cyclic protegrins.
复制标题
胱氨酸稳定的环状 protegrin 的膜溶解选择性。
DOI：
10.1046/j.1432-1327.2000.01359.x
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Yang,JL
中科院分区：
文献类型：
--
作者：
Tam,JP;Wu,C;Yang,JL
为了将构象刚性与抗菌活性和细胞毒性的溶膜选择性联系起来，我们制备了 protegrin-1 (PG-1) 的六种环状类似物，protegrin-1 是一种具有广谱抗菌活性的 18 残基阳离子肽。这些环状 protegrin 具有端到端肽键以及不同数量（零到三个）的跨链二硫键约束。最受限制的类似物是环状三胱氨酸protegrin (ccPG3)，含有三个均匀间隔的平行二硫键。在低盐和高盐条件下针对 10 种生物体的抗菌测定表明，这些环状 protegrin 对革兰氏阳性和革兰氏阴性细菌、真菌以及一种测试病毒 HIV-1 具有广泛的活性，具有不同的抗菌谱。与 PG-1 相比，环状三胱氨酸 ccPG3 对人类细胞的溶血活性降低了约 10 倍，对 10 种测试生物体中的 6 种的溶膜选择性提高了 6 至 30 倍。相比之下，[ΔSS]cPG8（一种没有二硫键的环状protegrin）和[ΔCys6,15]cPG5（一种具有一个二硫键的PG-1的环状模拟物）表现出与PG-1相似的活性谱、效力和细胞毒性。圆二色性表明，含有一到三个胱氨酸键的环状protegrin在水/三氟乙醇或磷酸盐缓冲溶液中表现出一定程度的β链结构。总的来说，我们的结果表明环状结构可用于抗菌肽的设计，并且 protegrin 构象刚性的增加可能会赋予膜溶解选择性，从而将抗菌活性与溶血活性分离。
To correlate conformational rigidity with membranolytic selectivity of antimicrobial activity and cytotoxicity, we prepared six cyclic analogs of protegrin‐1 (PG‐1), an 18‐residue cationic peptide with a broad‐spectrum antimicrobial activity. These cyclic protegrins bear end‐to‐end peptide bonds together with varying numbers (zero to three) of cross‐strand disulfide constraints. The most constrained analog is a cyclic tricystine protegrin (ccPG3) containing three evenly spaced, parallel disulfide bonds. Antimicrobial assays against 10 organisms in low‐ and high‐salt conditions showed that these cyclic protegrins were broadly active with different antimicrobial profiles against Gram‐positive and Gram‐negative bacteria, fungi and one tested virus, HIV‐1. Compared to PG‐1, the cyclic tricystine ccPG3displayed approximately a 10‐fold decrease in hemolytic activity against human cells and 6‐ to 30‐fold improvement of membranolytic selectivity against six of the 10 tested organisms. In contrast, [ΔSS]cPG8, a cyclic protegrin with no disulfide bond, and [ΔCys6,15]cPG5, a cyclic mimic of PG‐1 with one disulfide bond, exhibited activity spectra, potency, and cytotoxicity similar to PG‐1. Circular dichroism showed that cyclic protegrins containing with one to three cystine bonds displayed some degree of β‐strand structures in water/trifluoroethanol or phosphate‐buffered solutions. Collectively, our results indicate that cyclic structures are useful in the design of antimicrobial peptides and that an increase in the conformational rigidity of protegrins may confer membranolytic selectivity that dissociates antimicrobial activity from hemolytic activity.