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

Kemisk Institut

9 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	European Journal of Medicinal Chemistry
Vol/bind	102
Sider (fra-til)	574-581
Antal sider	8
ISSN	0223-5234
DOI	https://doi.org/10.1016/j.ejmech.2015.08.028
Status	Udgivet - 18 sep. 2015

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10.1016/j.ejmech.2015.08.028

Citationsformater

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.
I: European Journal of Medicinal Chemistry, Bind 102, 18.09.2015, s. 574-581.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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AU - Oddo, Alberto

AU - Nyberg, Nils

AU - Frimodt-Møller, Niels

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

M3 - Journal article

C2 - 26318064

SN - 0223-5234

VL - 102

SP - 574

EP - 581

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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