Alternating Cationic-Hydrophobic Peptide/Peptoid Hybrids: Influence of Hydrophobicity on Antibacterial Activity and Cell Selectivity
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Alternating Cationic-Hydrophobic Peptide/Peptoid Hybrids : Influence of Hydrophobicity on Antibacterial Activity and Cell Selectivity. / Frederiksen, Nicki; Hansen, Paul R; Zabicka, Dorota; Tomczak, Magdalena; Urbas, Malgorzata; Domraceva, Ilona; Björkling, Fredrik; Franzyk, Henrik.
I: ChemMedChem, Bind 15, Nr. 24, 2020, s. 2544-2561.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Alternating Cationic-Hydrophobic Peptide/Peptoid Hybrids
T2 - Influence of Hydrophobicity on Antibacterial Activity and Cell Selectivity
AU - Frederiksen, Nicki
AU - Hansen, Paul R
AU - Zabicka, Dorota
AU - Tomczak, Magdalena
AU - Urbas, Malgorzata
AU - Domraceva, Ilona
AU - Björkling, Fredrik
AU - Franzyk, Henrik
N1 - © 2020 Wiley-VCH GmbH.
PY - 2020
Y1 - 2020
N2 - The influence of hydrophobicity on antibacterial activity versus the effect on the viability of mammalian cells for peptide/peptoid hybrids was examined for oligomers based on the cationic Lys-like peptoid residue combined with each of 28 hydrophobic amino acids in an alternating sequence. Their relative hydrophobicity was correlated to activity against both Gram-negative and Gram-positive species, human red blood cells, and HepG2 cells. This identified hydrophobic side chains that confer potent antibacterial activity (e. g., MICs of 2-8 μg/mL against E. coli) and low toxicity toward mammalian cells (<10 % hemolysis at 400 μg/mL and IC50 >800 μg/mL for HepG2 viability). Most peptidomimetics retained activity against drug-resistant strains. These findings corroborate the hypothesis that for related peptidomimetics two hydrophobicity thresholds may be identified: i) it should exceed a certain level in order to confer antibacterial activity, and ii) there is an upper limit, beyond which cell selectivity is lost. It is envisioned that once identified for a given subclass of peptide-like antibacterials such thresholds can guide further optimisation.
AB - The influence of hydrophobicity on antibacterial activity versus the effect on the viability of mammalian cells for peptide/peptoid hybrids was examined for oligomers based on the cationic Lys-like peptoid residue combined with each of 28 hydrophobic amino acids in an alternating sequence. Their relative hydrophobicity was correlated to activity against both Gram-negative and Gram-positive species, human red blood cells, and HepG2 cells. This identified hydrophobic side chains that confer potent antibacterial activity (e. g., MICs of 2-8 μg/mL against E. coli) and low toxicity toward mammalian cells (<10 % hemolysis at 400 μg/mL and IC50 >800 μg/mL for HepG2 viability). Most peptidomimetics retained activity against drug-resistant strains. These findings corroborate the hypothesis that for related peptidomimetics two hydrophobicity thresholds may be identified: i) it should exceed a certain level in order to confer antibacterial activity, and ii) there is an upper limit, beyond which cell selectivity is lost. It is envisioned that once identified for a given subclass of peptide-like antibacterials such thresholds can guide further optimisation.
U2 - 10.1002/cmdc.202000526
DO - 10.1002/cmdc.202000526
M3 - Journal article
C2 - 33029927
VL - 15
SP - 2544
EP - 2561
JO - Farmaco
JF - Farmaco
SN - 1860-7179
IS - 24
ER -
ID: 249696346