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

Alberto Oddo; Nils Nyberg; Niels Frimodt-Møller; Peter Waaben Thulstrup; Paul Robert Hansen

doi:10.1016/j.ejmech.2015.08.028

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

Alberto Oddo, Nils Nyberg, Niels Frimodt-Møller, Peter Waaben Thulstrup, Paul Robert Hansen

Department of Chemistry

9 Citations (Scopus)

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.

Original language	English
Journal	European Journal of Medicinal Chemistry
Volume	102
Pages (from-to)	574-581
Number of pages	8
ISSN	0223-5234
DOIs	https://doi.org/10.1016/j.ejmech.2015.08.028
Publication status	Published - 18 Sept 2015

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The effect of glycine replacement with flexible ω-amino acids on the antimicrobial and haemolytic activity of an amphipathic cyclic heptapeptide. / Oddo, Alberto; Nyberg, Nils; Frimodt-Møller, Niels et al.
In: European Journal of Medicinal Chemistry, Vol. 102, 18.09.2015, p. 574-581.

Research output: Contribution to journal › Journal article › Research › peer-review

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AU - Nyberg, Nils

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AU - Thulstrup, Peter Waaben

AU - Hansen, Paul Robert

PY - 2015/9/18

Y1 - 2015/9/18

N2 - 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.

AB - 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.

U2 - 10.1016/j.ejmech.2015.08.028

DO - 10.1016/j.ejmech.2015.08.028

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JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

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

Abstract

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