Structure-Function Characteristics and Signaling Properties of Lipidated Peptidomimetic FPR2 Agonists: Peptoid Stereochemistry and Residues in the Vicinity of the Headgroup Affect Function

Andre Holdfeldt; Sarah Line Skovbakke; Michael Gabl; Christina Nielsen; Claes Dahlgren; Henrik Franzyk; Huamei Forsman

doi:10.1021/acsomega.9b00098

Structure-Function Characteristics and Signaling Properties of Lipidated Peptidomimetic FPR2 Agonists: Peptoid Stereochemistry and Residues in the Vicinity of the Headgroup Affect Function

Andre Holdfeldt, Sarah Line Skovbakke, Michael Gabl, Christina Nielsen, Claes Dahlgren, Henrik Franzyk^*, Huamei Forsman

^*Corresponding author af dette arbejde

8 Citationer (Scopus)

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Abstract

Formyl peptide receptor 2 (FPR2) plays important roles in inflammation. In the present study, 20 analogues of the FPR2-selective lipidated α-peptide/β-peptoid agonist Lau-[(S)-Aoc]-[Lys-βNPhe] ₆ -NH ₂ were generated, which allowed two novel subclasses of more potent FPR2 agonists to be distinguished. Critical factors influencing FPR2 recognition comprise the presence of β-peptoid phenylalanine-like residues (i.e., βNPhe, βNspe, or βNrpe) in the peptidomimetic tail, configuration of the 2-Aminooctanoic acid (Aoc) in the headgroup, and the length of the N-Terminal fatty acid. Intriguingly, a single βNrpe residue in the vicinity of the N-Terminus (i.e., Lau-[(S)-Aoc]-Lys-βNrpe-[Lys-βNPhe] ₅ -NH ₂ ) proved to increase the agonist potency, whereas the βNspe-containing analogue was a weak FPR2-selective antagonist. Another subclass displaying potent agonism comprised analogues possessing two α-Amino acids vicinal to the headgroup. The optimized FPR2-Activating lipidated peptidomimetics exhibited biased signaling: PLC-PIP ₂ -Ca ²⁺ signaling was activated, but without recruitment of β-Arrestin or induction of chemotaxis. These FPR2-interacting compounds are considered to be useful tools in future studies of receptor-ligand interactions.

Originalsprog	Engelsk
Tidsskrift	ACS Omega
Vol/bind	4
Udgave nummer	3
Sider (fra-til)	5968-5982
Antal sider	15
ISSN	2470-1343
DOI	https://doi.org/10.1021/acsomega.9b00098
Status	Udgivet - 28 mar. 2019

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10.1021/acsomega.9b00098Licens: CC BY-NC

acsomega.9b00098Forlagets udgivne version, 1,9 MBLicens: CC BY-NC

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Structure-Function Characteristics and Signaling Properties of Lipidated Peptidomimetic FPR2 Agonists : Peptoid Stereochemistry and Residues in the Vicinity of the Headgroup Affect Function. / Holdfeldt, Andre; Skovbakke, Sarah Line; Gabl, Michael et al.

I: ACS Omega, Bind 4, Nr. 3, 28.03.2019, s. 5968-5982.

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

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title = "Structure-Function Characteristics and Signaling Properties of Lipidated Peptidomimetic FPR2 Agonists: Peptoid Stereochemistry and Residues in the Vicinity of the Headgroup Affect Function",

abstract = " Formyl peptide receptor 2 (FPR2) plays important roles in inflammation. In the present study, 20 analogues of the FPR2-selective lipidated α-peptide/β-peptoid agonist Lau-[(S)-Aoc]-[Lys-βNPhe] 6 -NH 2 were generated, which allowed two novel subclasses of more potent FPR2 agonists to be distinguished. Critical factors influencing FPR2 recognition comprise the presence of β-peptoid phenylalanine-like residues (i.e., βNPhe, βNspe, or βNrpe) in the peptidomimetic tail, configuration of the 2-Aminooctanoic acid (Aoc) in the headgroup, and the length of the N-Terminal fatty acid. Intriguingly, a single βNrpe residue in the vicinity of the N-Terminus (i.e., Lau-[(S)-Aoc]-Lys-βNrpe-[Lys-βNPhe] 5 -NH 2 ) proved to increase the agonist potency, whereas the βNspe-containing analogue was a weak FPR2-selective antagonist. Another subclass displaying potent agonism comprised analogues possessing two α-Amino acids vicinal to the headgroup. The optimized FPR2-Activating lipidated peptidomimetics exhibited biased signaling: PLC-PIP 2 -Ca 2+ signaling was activated, but without recruitment of β-Arrestin or induction of chemotaxis. These FPR2-interacting compounds are considered to be useful tools in future studies of receptor-ligand interactions. ",

author = "Andre Holdfeldt and Skovbakke, {Sarah Line} and Michael Gabl and Christina Nielsen and Claes Dahlgren and Henrik Franzyk and Huamei Forsman",

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T2 - Peptoid Stereochemistry and Residues in the Vicinity of the Headgroup Affect Function

AU - Holdfeldt, Andre

AU - Skovbakke, Sarah Line

AU - Gabl, Michael

AU - Nielsen, Christina

AU - Dahlgren, Claes

AU - Franzyk, Henrik

AU - Forsman, Huamei

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N2 - Formyl peptide receptor 2 (FPR2) plays important roles in inflammation. In the present study, 20 analogues of the FPR2-selective lipidated α-peptide/β-peptoid agonist Lau-[(S)-Aoc]-[Lys-βNPhe] 6 -NH 2 were generated, which allowed two novel subclasses of more potent FPR2 agonists to be distinguished. Critical factors influencing FPR2 recognition comprise the presence of β-peptoid phenylalanine-like residues (i.e., βNPhe, βNspe, or βNrpe) in the peptidomimetic tail, configuration of the 2-Aminooctanoic acid (Aoc) in the headgroup, and the length of the N-Terminal fatty acid. Intriguingly, a single βNrpe residue in the vicinity of the N-Terminus (i.e., Lau-[(S)-Aoc]-Lys-βNrpe-[Lys-βNPhe] 5 -NH 2 ) proved to increase the agonist potency, whereas the βNspe-containing analogue was a weak FPR2-selective antagonist. Another subclass displaying potent agonism comprised analogues possessing two α-Amino acids vicinal to the headgroup. The optimized FPR2-Activating lipidated peptidomimetics exhibited biased signaling: PLC-PIP 2 -Ca 2+ signaling was activated, but without recruitment of β-Arrestin or induction of chemotaxis. These FPR2-interacting compounds are considered to be useful tools in future studies of receptor-ligand interactions.

AB - Formyl peptide receptor 2 (FPR2) plays important roles in inflammation. In the present study, 20 analogues of the FPR2-selective lipidated α-peptide/β-peptoid agonist Lau-[(S)-Aoc]-[Lys-βNPhe] 6 -NH 2 were generated, which allowed two novel subclasses of more potent FPR2 agonists to be distinguished. Critical factors influencing FPR2 recognition comprise the presence of β-peptoid phenylalanine-like residues (i.e., βNPhe, βNspe, or βNrpe) in the peptidomimetic tail, configuration of the 2-Aminooctanoic acid (Aoc) in the headgroup, and the length of the N-Terminal fatty acid. Intriguingly, a single βNrpe residue in the vicinity of the N-Terminus (i.e., Lau-[(S)-Aoc]-Lys-βNrpe-[Lys-βNPhe] 5 -NH 2 ) proved to increase the agonist potency, whereas the βNspe-containing analogue was a weak FPR2-selective antagonist. Another subclass displaying potent agonism comprised analogues possessing two α-Amino acids vicinal to the headgroup. The optimized FPR2-Activating lipidated peptidomimetics exhibited biased signaling: PLC-PIP 2 -Ca 2+ signaling was activated, but without recruitment of β-Arrestin or induction of chemotaxis. These FPR2-interacting compounds are considered to be useful tools in future studies of receptor-ligand interactions.

U2 - 10.1021/acsomega.9b00098

DO - 10.1021/acsomega.9b00098

M3 - Journal article

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ER -

Structure-Function Characteristics and Signaling Properties of Lipidated Peptidomimetic FPR2 Agonists: Peptoid Stereochemistry and Residues in the Vicinity of the Headgroup Affect Function

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