posted on 2021-01-19, 17:37authored byThissa
N. Siriwardena, Bee-Ha Gan, Thilo Köhler, Christian van Delden, Sacha Javor, Jean-Louis Reymond
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.