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设计具有改善抗菌选择性的Protegrin-1类似物

Ilia A Bolosov¹, Pavel V Panteleev¹, Sergei V Sychev¹

¹M. M. Shemyakin & Yu. A. Ovchinnikov Institute of Bioorganic Chemistry, the Russian Academy of Sciences, 117997 Moscow, Russia.

|August 26, 2023

概括

研究人员修改了抗微生物Protegrin-1 (PG-1),以减少其对人类细胞的毒性. 一种新的类似物,[V16R],保持强大的抗菌活性,同时显著降低溶血效应,提供更安全的抗生素候选者.

科学领域:

生物化学生物化学
微生物学微生物学
药物发现药物发现药物发现

背景情况:

普罗特格林-1 (PG-1) 是一种强大的抗微生物,对抗多药耐药性病原体有效.
高血解活性和细胞毒性限制了PG-1的治疗用途.
开发更安全的抗菌剂对于对抗耐药性感染至关重要.

研究的目的:

设计和表征Protegrin-1类似物,降低哺乳动物细胞毒性,同时保持抗微生物疗效.
确定特定的氨基酸替代物,以改善PG-1的治疗指数.

主要方法:

合理设计PG-1类似物通过替代中央β-sheet区域的残留物来调节电荷和疏水性.
使用Escherichia coli*中的氧化物生产类似物.
评估野生型PG-1及其类型的抗菌活性,血液溶解活性和细胞毒性.

主要成果:

在C端β链中单个氨基酸替代 (V16R) 显著降低了溶血活性,而不会影响抗菌作用.
与野生型PG-1相比,同类型[V16R]的治疗指数改善了≥30倍.
FTIR分析表明[V16R]在模仿膜的环境中不形成寡合结构,与野生类型PG-1不同.

结论:

PG-1模拟物[V16R]具有良好的安全性和强大的抗菌活性,使其成为一个有前途的化合物.
通过特定的替代物调节PG-1的寡合化,可以将抗菌作用与哺乳动物细胞毒性脱.
[V16R]在小鼠败血症模型中显示出有效性,支持其用于全身抗生素开发的潜力.

关键词:

抗微生物是一种抗微生物.凯瑟利西西丁的存在氧化聚合物的一种.保护人-1 保护人-1 治疗指数治疗指数

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