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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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; Nielsen, Christina; Dahlgren, Claes; Franzyk, Henrik; Forsman, Huamei.
I: ACS Omega, Bind 4, Nr. 3, 28.03.2019, s. 5968-5982.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Structure-Function Characteristics and Signaling Properties of Lipidated Peptidomimetic FPR2 Agonists
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
PY - 2019/3/28
Y1 - 2019/3/28
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
AN - SCOPUS:85063580267
VL - 4
SP - 5968
EP - 5982
JO - ACS Omega
JF - ACS Omega
SN - 2470-1343
IS - 3
ER -
ID: 216925053