Publication

Back to overview

Stereorandomization as a Method to Probe Peptide Bioactivity

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Siriwardena Thissa N., Gan Bee-Ha, Köhler Thilo, van Delden Christian, Javor Sacha, Reymond Jean-Louis,
Project Chemical Space Design of Small Molecules and Peptides
Show all

Original article (peer-reviewed)

Journal ACS Central Science
Volume (Issue) 7(1)
Page(s) 126 - 134
Title of proceedings ACS Central Science
DOI 10.1021/acscentsci.0c01135

Abstract

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.
-