Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Freiestrasse 3, CH-3012 Bern, Switzerland.
Department of Microbiology and Molecular Medicine, University of Geneva, CH-1211 Geneva, Switzerland.
J Med Chem. 2023 Jun 8;66(11):7570-7583. doi: 10.1021/acs.jmedchem.3c00460. Epub 2023 May 25.
Membrane disruptive α-helical antimicrobial peptides (AMPs) offer an opportunity to address multidrug resistance; however, most AMPs are toxic and unstable in serum. These limitations can be partly overcome by introducing D-residues, which often confers protease resistance and reduces toxicity without affecting antibacterial activity, presumably due to lowered α-helicity. Here, we investigated 31 diastereomers of the α-helical AMP KKLLKLLKLLL. Three diastereomers containing two, three, and four D-residues showed increased antibacterial effects, comparable hemolysis, reduced toxicity against HEK293 cells, and excellent serum stability, while another diastereomer with four D-residues additionally displayed lower hemolysis. X-ray crystallography confirmed that high or low α-helicity as measured by circular dichroism indicated α-helical or disordered structures independently of the number of chirality switched residues. In contrast to previous reports, α-helicity across diastereomers correlated with both antibacterial activity and hemolysis and revealed a complex relationship between stereochemistry, activity, and toxicity, highlighting the potential of diastereomers for property optimization.
膜破坏型 α-螺旋抗菌肽 (AMPs) 为解决多重耐药性提供了机会; 然而，大多数 AMPs 在血清中具有毒性和不稳定性。通过引入 D-残基可以部分克服这些限制，这通常赋予蛋白酶抗性并降低毒性而不影响抗菌活性，推测是由于 α-螺旋性降低。在这里，我们研究了 31 种 α-螺旋 AMP KKLLKLLKLLL 的非对映异构体。含有两个、三个和四个 D-残基的三个非对映异构体显示出增强的抗菌效果、相当的溶血作用、降低对 HEK293 细胞的毒性以及优异的血清稳定性，而另一个含有四个 D-残基的非对映异构体则显示出更低的溶血作用。X 射线晶体学证实，圆二色性测量的高或低 α-螺旋性独立于手性转换残基的数量指示 α-螺旋或无定形结构。与之前的报道相反，非对映异构体之间的 α-螺旋性与抗菌活性和溶血作用相关，并揭示了立体化学、活性和毒性之间的复杂关系，突出了非对映异构体在性质优化方面的潜力。
