Solid-phase peptide synthesis (SPPS) is usually performed with optically pure building blocks to prepare peptides as single enantiomers. Herein we report that SPPS using racemic amino acids provides stereorandomized (sr) peptides, containing up to billions of different stereoisomers, as well-defined single HPLC peaks, single mass products with high yield, which can be used to investigate peptide bioactivity. To exemplify our method, we show that stereorandomization abolishes the membrane-disruptive effect of α-helical amphiphilic antimicrobial peptides but preserves their antibiofilm effect, implying different mechanisms involving folded versus disordered conformations. For antimicrobial peptide dendrimers by contrast, stereorandomization preserves antibacterial, membrane-disruptive, and antibiofilm effects but reduces hemolysis and cytotoxicity, thereby increasing their therapeutic index. Finally, we identify partially stereorandomized analogues of the last resort cyclic peptide antibiotic polymyxin B with preserved antibacterial activity but lacking membrane-disruptive and lipopolysaccharide-neutralizing activity, pointing to the existence of additional targets.

中文翻译：

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立体随机化作为探测肽生物活性的方法

固相肽合成（SPPS）通常用光学纯的结构单元进行，以将肽制备为单一对映体。在此，我们报道使用外消旋氨基酸的SPPS提供了立体随机化（sr）包含多达数十亿种不同立体异构体的肽，以及定义明确的单个HPLC峰，高产率的单一质量产品，可用于研究肽的生物活性。为了举例说明我们的方法，我们显示了立体随机化消除了α螺旋两亲性抗菌肽的破坏膜作用，但保留了其抗生物膜作用，暗示了涉及折叠与无序构象的不同机制。相比之下，对于抗菌肽树状聚合物，立体随机化保留了抗菌，破坏膜和抗生​​物膜的作用，但减少了溶血作用和细胞毒性，从而提高了它们的治疗指数。最后，