人类LL-37片段的溶液结构和基于NMR的最小膜向抗微生物和抗癌区域的识别.

Xia Li¹, Yifeng Li, Huiyun Han

¹Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA.

Journal of the American Chemical Society

|April 28, 2006

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研究人员确定了人类LL-37的核心片段,具有强大的抗菌和抗癌活性. 将D-氨基酸纳入这个片段,通过创建结构缺陷来增强细胞选择性,减少人类细胞的毒性,同时保持对细菌和癌细胞的有效性.

科学领域:

生物化学生物化学
结构生物学结构生物学
抗微生物是一种抗菌.

背景情况:

人类甲基素LL-37是一种具有广泛活性的关键抗微生物.
了解LL-37的结构-活性关系对于开发新型治疗剂至关重要.
LL-37的作用机制涉及与细菌膜的相互作用.

研究的目的:

描述LL-37抗微生物和抗癌活动的结构基础.
为了识别最小的片,保留LL-37.的基本功能.
为了改造LL-37片段,提高对目标细胞的选择性.

主要方法:

的设计和合成LL-37碎片.
核磁共振 (NMR) 光谱法用于确定小粒体中的三维结构.
通过切割非重要区域 (TOCSY-trim) 进行总相关光谱,用于碎片识别.
加入D-氨基酸来评估对活性和选择性的影响.
逆相高性能液态染色学 (RP-HPLC) 用于结构分析.

主要成果:

一种13余核 (LL-37(17-29) 显示出显著的抗菌和抗癌活性.
核磁共振结构分析显示,在模仿膜的环境中,存在两形螺旋结构.

C端片段 (LL-37 ......13-37) 和核心具有相似的结构特征.

将D-氨基酸纳入LL-37 (((17-32) 产生了一种D-,其抗菌活性保持,但对人体细胞有毒性降低.

对D-的结构分析揭示了疏水缺陷,有助于增强细胞选择性.

结论:

C终端区域和一个特定的13个残留物核心对LL-37的生物活性至关重要.
在模仿膜的环境中,两形螺旋结构在活性碎片中得到保存.
加入D-氨基酸是一种可行的策略,可以提高LL-37基的治疗指数.
由D-氨基酸引入的疏水缺陷是实现选择性膜向和降低宿主细胞毒性的关键.

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科学领域:

背景情况:

研究的目的:

主要方法:

主要成果:

结论: