Lipidated α-Peptide/β-Peptoid Hybrids with Potent Anti-inflammatory Activity

Sarah Line Skovbakke; Camilla Josephine Larsen; Peter Mikael Helweg Heegaard; Lise Moesby; Henrik Franzyk

doi:10.1021/jm501341h

Lipidated α-Peptide/β-Peptoid Hybrids with Potent Anti-inflammatory Activity

Sarah Line Skovbakke, Camilla Josephine Larsen, Peter Mikael Helweg Heegaard, Lise Moesby, Henrik Franzyk

16 Citations (Scopus)

Abstract

In this study, we investigated, optimized, and characterized a novel subclass of host defense peptide (HDP) mimics based on α-peptide/β-peptoid hybrid oligomers with an alternating cationic/hydrophobic design with respect to their ability to modulate the pro-inflammatory response by human primary leukocytes upon exposure to bacterial components. Structure-activity studies revealed that certain lipidated α-peptide/β-peptoid hybrid oligomers possess anti-inflammatory activities in the submicromolar range with low cytotoxicity, and that the anti-inflammatory activity of the HDP mimics is dependent on the length and position of the lipid element(s). The resulting lead compound, Pam-(Lys-βNSpe)₆-NH₂, blocks LPS-induced cytokine secretion with a potency comparable to that of polymyxin B. The mode of action of this HDP mimic appears not to involve direct LPS interaction since it, in contrast to polymyxin B, displayed only minor activity in the Limulus amebocyte lysate assay. Flow cytometry data showed specific interaction of a fluorophore-labeled lipidated α-peptide/β-peptoid hybrid with monocytes and granulocytes indicating a cellular target expressed by these leukocyte subsets.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	58
Issue number	2
Pages (from-to)	801-813
Number of pages	13
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm501341h
Publication status	Published - 22 Jan 2015

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title = "Lipidated α-Peptide/β-Peptoid Hybrids with Potent Anti-inflammatory Activity",

abstract = "In this study, we investigated, optimized, and characterized a novel subclass of host defense peptide (HDP) mimics based on α-peptide/β-peptoid hybrid oligomers with an alternating cationic/hydrophobic design with respect to their ability to modulate the pro-inflammatory response by human primary leukocytes upon exposure to bacterial components. Structure-activity studies revealed that certain lipidated α-peptide/β-peptoid hybrid oligomers possess anti-inflammatory activities in the submicromolar range with low cytotoxicity, and that the anti-inflammatory activity of the HDP mimics is dependent on the length and position of the lipid element(s). The resulting lead compound, Pam-(Lys-βNSpe)6-NH2, blocks LPS-induced cytokine secretion with a potency comparable to that of polymyxin B. The mode of action of this HDP mimic appears not to involve direct LPS interaction since it, in contrast to polymyxin B, displayed only minor activity in the Limulus amebocyte lysate assay. Flow cytometry data showed specific interaction of a fluorophore-labeled lipidated α-peptide/β-peptoid hybrid with monocytes and granulocytes indicating a cellular target expressed by these leukocyte subsets.",

author = "Skovbakke, {Sarah Line} and Larsen, {Camilla Josephine} and Heegaard, {Peter Mikael Helweg} and Lise Moesby and Henrik Franzyk",

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T1 - Lipidated α-Peptide/β-Peptoid Hybrids with Potent Anti-inflammatory Activity

AU - Skovbakke, Sarah Line

AU - Larsen, Camilla Josephine

AU - Heegaard, Peter Mikael Helweg

AU - Moesby, Lise

AU - Franzyk, Henrik

PY - 2015/1/22

Y1 - 2015/1/22

N2 - In this study, we investigated, optimized, and characterized a novel subclass of host defense peptide (HDP) mimics based on α-peptide/β-peptoid hybrid oligomers with an alternating cationic/hydrophobic design with respect to their ability to modulate the pro-inflammatory response by human primary leukocytes upon exposure to bacterial components. Structure-activity studies revealed that certain lipidated α-peptide/β-peptoid hybrid oligomers possess anti-inflammatory activities in the submicromolar range with low cytotoxicity, and that the anti-inflammatory activity of the HDP mimics is dependent on the length and position of the lipid element(s). The resulting lead compound, Pam-(Lys-βNSpe)6-NH2, blocks LPS-induced cytokine secretion with a potency comparable to that of polymyxin B. The mode of action of this HDP mimic appears not to involve direct LPS interaction since it, in contrast to polymyxin B, displayed only minor activity in the Limulus amebocyte lysate assay. Flow cytometry data showed specific interaction of a fluorophore-labeled lipidated α-peptide/β-peptoid hybrid with monocytes and granulocytes indicating a cellular target expressed by these leukocyte subsets.

AB - In this study, we investigated, optimized, and characterized a novel subclass of host defense peptide (HDP) mimics based on α-peptide/β-peptoid hybrid oligomers with an alternating cationic/hydrophobic design with respect to their ability to modulate the pro-inflammatory response by human primary leukocytes upon exposure to bacterial components. Structure-activity studies revealed that certain lipidated α-peptide/β-peptoid hybrid oligomers possess anti-inflammatory activities in the submicromolar range with low cytotoxicity, and that the anti-inflammatory activity of the HDP mimics is dependent on the length and position of the lipid element(s). The resulting lead compound, Pam-(Lys-βNSpe)6-NH2, blocks LPS-induced cytokine secretion with a potency comparable to that of polymyxin B. The mode of action of this HDP mimic appears not to involve direct LPS interaction since it, in contrast to polymyxin B, displayed only minor activity in the Limulus amebocyte lysate assay. Flow cytometry data showed specific interaction of a fluorophore-labeled lipidated α-peptide/β-peptoid hybrid with monocytes and granulocytes indicating a cellular target expressed by these leukocyte subsets.

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DO - 10.1021/jm501341h

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SN - 0022-2623

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EP - 813

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 2

ER -

Lipidated α-Peptide/β-Peptoid Hybrids with Potent Anti-inflammatory Activity

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