Department of Inorganic Chemistry, Faculty of Pharmacy, Medical University of Gdańsk, 80-416 Gdańsk, Poland.
Department of Organic Chemistry, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland.
Int J Mol Sci. 2020 Sep 29;21(19):7208. doi: 10.3390/ijms21197208.
Ultrashort cationic lipopeptides (USCLs) are considered to be a promising class of antimicrobials with high activity against a broad-spectrum of microorganisms. However, the majority of these compounds are characterized by significant toxicity toward human cells, which hinders their potential application. To overcome those limitations, several approaches have been advanced. One of these is disulfide cyclization that has been shown to improve drug-like characteristics of peptides. In this article the effect of disulfide cyclization of the polar head of -palmitoylated USCLs on in vitro biological activity has been studied. Lipopeptides used in this study consisted of three or four basic amino acids (lysine and arginine) and cystine in a cyclic peptide. In general, disulfide cyclization of the lipopeptides resulted in peptides with reduced cytotoxicity. Disulfide-cyclized USCLs exhibited improved selectivity between sp., Gram-positive strains and normal cells in contrast to their linear counterparts. Interactions between selected USCLs and membranes were studied by molecular dynamics simulations using a coarse-grained force field. Moreover, membrane permeabilization properties and kinetics were examined. Fluorescence and transmission electron microscopy revealed damage to cell membrane and organelles. Concluding, USCLs are strong membrane disruptors and disulfide cyclization of polar head can have a beneficial effect on its in vitro selectivity between sp. and normal human cells.
超短阳离子脂肽（USCL）被认为是一类很有前途的抗菌剂，对广谱微生物具有高活性。然而，这些化合物中的大多数对人类细胞具有显著的毒性，这阻碍了它们的潜在应用。为了克服这些限制，已经提出了几种方法。其中之一是二硫键环化，已证明它可以改善肽的类药性。在本文中，研究了 -棕榈酰化 USCL 极性头的二硫键环化对体外生物活性的影响。本研究中使用的脂肽由三个或四个碱性氨基酸（赖氨酸和精氨酸）和半胱氨酸组成的环状肽。一般来说，脂肽的二硫键环化导致细胞毒性降低的肽。与线性对应物相比，二硫键环化的 USCL 表现出在革兰氏阳性菌株和正常细胞之间更高的选择性。通过使用粗粒度力场的分子动力学模拟研究了选定的 USCL 与膜之间的相互作用。此外，还研究了膜通透性和动力学。荧光和透射电子显微镜揭示了细胞膜和细胞器的损伤。总之，USCL 是强大的膜破坏剂，二硫键环化极性头可以对其在革兰氏阳性菌和正常人类细胞之间的体外选择性产生有益影响。
