Reymond Research Group

University of Bern

Stereorandomization as a Method to Probe Peptide Bioactivity

The research article "Stereorandomization as a method to probe peptide bioactivity" was just published in ACS Central Science.

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 peak, 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 anti-biofilm effects but reduces hemolysis and cytotoxicity, thereby increasing their therapeutic index. Finally, we identify partially stereorandomized analogs 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.

Author(s): Thissa N. Siriwardena, Bee-Ha Gan, Thilo Köhler, Christian van Delden, Sacha Javor and Jean-Louis Reymond