人 LL-37 片段的溶液结构和基于 NMR 的最小膜靶向抗菌和抗癌区域的鉴定,Journal of the American Chemical Society

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人 LL-37 片段的溶液结构和基于 NMR 的最小膜靶向抗菌和抗癌区域的鉴定
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2006-05-01 , DOI: 10.1021/ja0584875
Xia Li ₁ , Yifeng Li ₁ , Huiyun Han ₁ , Donald W. Miller ₁ , Guangshun Wang ₁

Affiliation

为了了解人LL-37的结构和活性关系，设计了一系列肽片段。N 端片段 LL-37(1-12) 没有活性，而 C 端片段 LL-37(13-37) 可杀死大肠杆菌以及药物敏感性和耐药性癌症细胞。基于总相关光谱法通过修剪非必要区域 (TOCSY-trim) 鉴定了 13 个残基的核心抗菌和抗癌肽，对应于 LL-37 的第 17-29 位残基。由于 LL-37 作用于细菌膜，因此通过 NMR 在胶束中确定了其片段的三维结构，包括通过自然丰度 15N 和 13C 化学位移进行的结构改进。N 端片段中的芳香-芳香相互作用被认为是 LL-37 聚集的必要条件。LL-37 核心肽在 SDS 或二辛酰基磷脂酰甘油的胶束中采用相似的结构。这种结构保留在 C 端片段 LL-37(13-37) 中，并且很可能保留在基于肽辅助信号分配的完整 LL-37 中。LL-37 核心肽比金黄素 1.2 更高的抗菌活性归因于额外的阳离子残基。为了实现选择性膜靶向，将 D-氨基酸并入 LL-37(17-32)。虽然 D-肽表现出与 L-非对映异构体相似的抗菌活性，但它对人体细胞失去了毒性。结构分析揭示了 D-肽的新两亲结构中的疏水缺陷，导致在反相 HPLC 柱上的保留时间要短得多。

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Solution Structures of Human LL-37 Fragments and NMR-Based Identification of a Minimal Membrane-Targeting Antimicrobial and Anticancer Region

To understand the structure and activity relationship of human LL-37, a series of peptide fragments was designed. The N-terminal fragment, LL-37(1-12), was not active, while the C-terminal fragment, LL-37(13-37), killed Escherichia coli, as well as drug-sensitive and drug-resistant cancer cells. A 13-residue core antibacterial and anticancer peptide, corresponding to residues 17-29 of LL-37, was identified based on total correlated spectroscopy by trimming nonessential regions (TOCSY-trim). Because LL-37 acts on bacterial membranes, three-dimensional structures of its fragments were determined in micelles by NMR, including structural refinement by natural abundance 15N and 13C chemical shifts. Aromatic-aromatic interactions in the N-terminal fragment were proposed to be essential for LL-37 aggregation. The LL-37 core peptide adopts a similar structure in the micelles of SDS or dioctanoyl phosphatidylglycerol. This structure is retained in the C-terminal fragment LL-37(13-37) and very likely in intact LL-37 based on peptide-aided signal assignments. The higher antibacterial activity of the LL-37 core peptide than aurein 1.2 was attributed to additional cationic residues. To achieve selective membrane targeting, D-amino acids were incorporated into LL-37(17-32). While the D-peptide showed similar antibacterial activity to the L-diastereomer, it lost toxicity to human cells. Structural analysis revealed hydrophobic defects in the new amphipathic structure of the D-peptide, leading to a much shorter retention time on a reversed-phase HPLC column. It is proposed that hydrophobic defects as a result of incoherent hydrophobic packing provide a structural basis for the improvement in cell selectivity of the LL-37 fragment.

更新日期：2006-05-01

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