title: The effect of glycine replacement with flexible ω-amino acids on the antimicrobial and haemolytic activity of an amphipathic cyclic heptapeptide.
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.
authors: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark. Electronic address: alberto.oddo@sund.ku.dk.
authors: Alberto
authors: A
authors: Oddo
authors: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
authors: Nils T
authors: NT
authors: Nyberg
authors: Department of Clinical Microbiology, Hvidovre Hospital, Kettegård Alle 30, 2650, Hvidovre, Denmark.
authors: Niels
authors: N
authors: Frimodt-Møller
authors: Department of Chemistry, University of Copenhagen, Universitetsparken 5, 2100, Copenhagen, Denmark.
authors: Peter W
authors: PW
authors: Thulstrup
authors: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark. Electronic address: prh@sund.ku.dk.
authors: Paul R
authors: PR
authors: Hansen
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005658:Fungi / Q000187:drug effects; D005998:Glycine / Q000737:chemistry*; D006461:Hemolysis / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013501:Surface-Active Agents / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000596:Amino Acids; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D010456:Peptides, Cyclic; D013501:Surface-Active Agents; D005998:Glycine
keywords: Antibiotics; Antimicrobial; Cyclic; Flexible; Peptides