Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland.
Department of Microbiology and Molecular Medicine, University of Geneva, Service of Infectious Diseases, University Hospital of Geneva, 1211 Geneva, Switzerland.
J Med Chem. 2024 Nov 14;67(21):19448-19459. doi: 10.1021/acs.jmedchem.4c01768. Epub 2024 Oct 24.
We recently showed that solid-phase peptide synthesis using racemic amino acids yields stereorandomized peptides comprising all possible diastereomers as homogeneous, single-mass products that can be purified by HPLC and that stereorandomization modulates activity, toxicity, and stability of membrane-disruptive cyclic and linear antimicrobial peptides (AMPs) and dendrimers. Here, we tested if stereorandomization might be compatible with target binding peptides with the example of the proline-rich AMP oncocin, which inhibits the bacterial ribosome. Stereorandomization of up to nine -terminal residues preserved ribosome binding and antibacterial effects including activities against drug-resistant bacteria and protected against serum degradation. Surprisingly, fully stereorandomized oncocin was as active as L-oncocin in dilute growth media stimulating peptide uptake, although it did not bind the ribosome, indicative of an alternative mechanism of action. These experiments show that stereorandomization can be compatible with target binding peptides and can help understand their mechanism of action.
我们最近表明，使用外消旋氨基酸的固相肽合成可产生立体随机化的肽，这些肽包含所有可能的非对映异构体，作为均相、单质量产物，可以通过 HPLC 进行纯化，并且立体随机化调节膜破坏的环状和线性抗菌肽 (AMP) 和树枝状聚合物的活性、毒性和稳定性。在这里，我们以富含脯氨酸的 AMP oncocin 为例测试了立体随机化是否与靶结合肽兼容，oncocin 抑制细菌核糖体。多达九个 -末端残基的立体随机化保留了核糖体结合和抗菌作用，包括对抗耐药菌的活性和防止血清降解。令人惊讶的是，完全立体随机化的 oncocin 在刺激肽摄取的稀生长培养基中与 L-oncocin 一样具有活性，尽管它不结合核糖体，表明存在替代作用机制。这些实验表明，立体随机化可以与靶结合肽兼容，并有助于了解它们的作用机制。
