Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland.
Department of Biosciences, Division of Microbiology, Paris Lodron University of Salzburg, Billrothstrasse 11, 5020 Salzburg, Austria.
Biochemistry. 2020 Oct 6;59(39):3772-3781. doi: 10.1021/acs.biochem.0c00565. Epub 2020 Sep 16.
Naturally occurring membranolytic antimicrobial peptides (AMPs) are rarely cell-type selective and highly potent at the same time. Template-based peptide design can be used to generate AMPs with improved properties . Following this approach, 18 linear peptides were obtained by computationally morphing the natural AMP Aurein 2.2d2 GLFDIVKKVVGALG into the synthetic model AMP KLLKLLKKLLKLLK. Eleven of the 18 chimeric designs inhibited the growth of , and six peptides were tested and found to be active against one resistant pathogenic strain or more. One of the peptides was broadly active against bacterial and fungal pathogens without exhibiting toxicity to certain human cell lines. Solution nuclear magnetic resonance and molecular dynamics simulation suggested an oblique-oriented membrane insertion mechanism of this helical peptide. Temperature-resolved circular dichroism spectroscopy pointed to conformational flexibility as an essential feature of cell-type selective AMPs.
天然存在的膜溶菌抗菌肽（AMPs）很少同时具有细胞类型选择性和高效性。基于模板的肽设计可用于生成具有改进特性的 AMPs。采用这种方法，通过计算将天然 AMP Aurein 2.2d2 GLFDIVKKVVGALG 变形为合成模型 AMP KLLKLLKKLLKLLK，得到了 18 条线性肽。在这 18 个嵌合设计中，有 11 个抑制了 的生长，其中 6 个肽被测试并发现对一种或多种耐药性病原菌有效。有一种肽对细菌和真菌病原体具有广泛的活性，而对某些人类细胞系没有毒性。溶液核磁共振和分子动力学模拟表明，这种螺旋肽具有斜向插入膜的机制。温度分辨圆二色性光谱指出，构象灵活性是细胞类型选择性 AMPs 的一个重要特征。
