深度突变扫描和机器学习揭示了驱动膜选择性的抗菌特征
Justin R Randall1, Luiz C Vieira2, Claus O Wilke2
1Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas 78712.
Research square
|October 4, 2023
概括
研究人员开发了深度突变表面局部化抗微生物显示器 (dmSLAY),以设计具有改善细菌特异性的抗微生物. 这种方法确定了序列修改,可以提高功效,同时最大限度地减少哺乳动物细胞损伤,为更安全的疗法铺平了道路.
科学领域:
- 生物化学和分子生物学
- 药物发现和开发 药物发现和开发
- 计算生物学 计算生物学
背景情况:
- 抗微生物 (AMP) 对于天生的免疫力至关重要,但通常会表现出宽膜破坏,影响微生物和宿主细胞.
- 了解AMP的序列结构功能关系对于开发具有降低毒性的向疗法至关重要.
- 以前的方法缺乏探索足够多的序列变异以进行全面分析的能力.
研究的目的:
- 开发一种高通量方法,深度突变表面局部抗微生物显示器 (dmSLAY),用于剖析抗微生物序列-结构-功能关系.
- 为了确定Protegrin-1的序列变异,增强抗菌活性和提高对哺乳动物膜的选择性.
- 为了利用机器学习进行大规模分析序列空间.
主要方法:
- 开发和应用深度突变表面局部化抗微生物显示 (dmSLAY) 到Protegrin-1.
- 识别和描述影响抗菌活性和膜特异性的序列变异.
- 整合dmSLAY数据与机器学习算法,分析超过570万个序列变异.
主要成果:
- dmSLAY成功地发现了数千种具有改变抗菌活性和选择性的Protegrin-1变体.
- 为了提高细菌特异性的关键序列修改包括避免大量的芳香残留物和二硫化物结合的氨酸,同时保持二级结构.
- 机器学习模型揭示了与细菌与哺乳动物膜特异性相关的全面突变特征.
结论:
- dmSLAY是一种创新的,高通量方法,用于阐明AMP序列结构功能关系.
- 特定的序列修改可以显著提高强效抗微生物的细菌选择性,如Protegrin-1.
- 这项工作为合理设计更安全,更有效的合成基抗菌药物提供了基础.
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