Potent antibacterial lysine-peptoid hybrids identified from a positional scanning combinatorial library.
In this paper, we describe the synthesis and screening of a biased positional scanning library made up of peptoids (N-alkylglycines) and lysines. The library consisted of 100 mixtures divided into four sub-libraries; OXXXKKK, XOXXKKK, XXOXKKK, and XXXOKKK, O being a defined peptoid building block and X a mixture of 25 peptoid building blocks. A theoretical number of 390,625 compounds were synthesized. The compound mixtures were screened against the American Type Culture Collection (ATCC) Staphylococcus aureus ATCC 25923 and Escherichia coli ATCC 25922 bacterial strains, and the cytotoxic activities were assessed using a human blood hemolytic assay. The results from each sub-library were examined to identify the most potent amine at each position. On the basis of this knowledge eight new lysine-peptoid hybrids were synthesized and tested in the biological assays. One compound in particular, [N-(cyclohexylmethyl)glycyl]-[N-(1-methylhexyl)glycyl]-[N-(4-methylbenzyl)glycyl]-[N-(2-(3-chlorophenyl)ethyl)glycyl]-lysyl-lysyl-lysine amide, showed high antibacterial activity and low toxicity toward red blood cells.
Ryge
Trine S
TS
Department of Natural Sciences, KVL, Frederiksberg, Copenhagen, Denmark.
Hansen
Paul R
PR
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D003510:Cyclohexanes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects*; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008239:Lysine / Q000737:chemistry; D034442:N-substituted Glycines / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D009842:Oligopeptides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D019151:Peptide Library; D034444:Peptoids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013211:Staphylococcus aureus / Q000187:drug effects*
C512500:(N-(cyclohexylmethyl)glycyl)-(N-(1-methylhexyl)glycyl)-(N-(4-methylbenzyl)glycyl)-(N-(2-(3-chlorophenyl)ethyl)glycyl)-lysyl-lysyl-lysine amide; D000900:Anti-Bacterial Agents; D003510:Cyclohexanes; D034442:N-substituted Glycines; D009842:Oligopeptides; D019151:Peptide Library; D034444:Peptoids; D008239:Lysine