The effect of glycine replacement with flexible ω-amino acids on the antimicrobial and haemolytic activity of an amphipathic cyclic heptapeptide

European Journal of Medicinal Chemistry
Alberto OddoPaul R Hansen

Abstract

Although cyclic peptide structures are usually investigated as highly constrained scaffolds, cyclic antimicrobial peptides of natural origin often feature flexible residues. Hereby we report our findings concerning a structure-activity study conducted on a model sequence by replacing a glycine residue with a variety of flexible residues (i.e. ω-amino and α,ω-diamino acids). The resulting library has been tested for antimicrobial activity against a wide range of clinically relevant pathogens as well as for toxicity to red blood cells. Circular dichroism and molecular modelling have been used to study changes in conformation. Increments as high as 16-fold in antimicrobial activity (as effective as lipidation) and >2-fold in haemolytic EC50 values were observed. Interestingly, secondary structures can be stabilized by increasing, rather than decreasing, ring flexibility.

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Citations

Nov 20, 2016·Chembiochem : a European Journal of Chemical Biology·Jonas WilbsChristian Heinis
Mar 15, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ines GrecoPaul R Hansen
Nov 20, 2016·Angewandte Chemie·Stefan J McCarverDavid W C MacMillan
Aug 14, 2020·Chemical Reviews·Rasha JwadLuke Hunter
Sep 25, 2021·Chemical Reviews·Lisa CandishSebastian Keess

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