Department of Organic Chemistry, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland.
Department of Physical Chemistry, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland.
Int J Mol Sci. 2023 Feb 16;24(4):3951. doi: 10.3390/ijms24043951.
In this paper, we describe the chemical synthesis, preliminary evaluation of antimicrobial properties and mechanisms of action of a novel group of lipidated derivatives of three naturally occurring α-helical antimicrobial peptides, LL-I (VNWKKVLGKIIKVAK-NH), LK6 (IKKILSKILLKKL-NH), ATRA-1 (KRFKKFFKKLK-NH). The obtained results showed that biological properties of the final compounds were defined both by the length of the fatty acid and by the structural and physico-chemical properties of the initial peptide. We consider C-C length of the hydrocarbon chain as the optimal for antimicrobial activity improvement. However, the most active analogues exerted relatively high cytotoxicity toward keratinocytes, with the exception of the ATRA-1 derivatives, which had a higher selectivity for microbial cells. The ATRA-1 derivatives had relatively low cytotoxicity against healthy human keratinocytes but high cytotoxicity against human breast cancer cells. Taking into account that ATRA-1 analogues carry the highest positive net charge, it can be assumed that this feature contributes to cell selectivity. As expected, the studied lipopeptides showed a strong tendency to self-assembly into fibrils and/or elongated and spherical micelles, with the least cytotoxic ATRA-1 derivatives forming apparently smaller assemblies. The results of the study also confirmed that the bacterial cell membrane is the target for the studied compounds.
在本文中，我们描述了一组新型脂质化衍生物的化学合成、抗菌性能的初步评价和作用机制，这些衍生物是由三种天然存在的α-螺旋抗菌肽 LL-I（VNWKKVLGKIIKVAK-NH）、LK6（IKKILSKILLKKL-NH）和 ATRA-1（KRFKKFFKKLK-NH）衍生而来。所得结果表明，最终化合物的生物学特性既由脂肪酸的长度决定，也由初始肽的结构和物理化学性质决定。我们认为碳-碳链的长度是提高抗菌活性的最佳选择。然而，最具活性的类似物对角质形成细胞表现出相对较高的细胞毒性，ATR-1 衍生物除外，其对微生物细胞具有更高的选择性。ATR-1 衍生物对健康人角质形成细胞的细胞毒性相对较低，但对人乳腺癌细胞的细胞毒性较高。考虑到 ATRA-1 类似物带有最高的净正电荷，可以假设这一特性有助于细胞选择性。正如预期的那样，研究中的脂肽表现出强烈的自组装成纤维和/或伸长和球形胶束的趋势，具有最低细胞毒性的 ATRA-1 衍生物形成的聚集体显然更小。研究结果还证实，细菌细胞膜是这些化合物的作用靶点。
