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Formyl peptide receptor 2 (FPR2) plays important roles in inflammation. In the present study, 20 analogues of the FPR2-selective lipidated alpha-peptide/beta-peptoid agonist Lau-[(S)-Aoc]-[Lys-beta NPhe](6)-NH2 were generated, which allowed two novel subclasses of more potent FPR2 agonists to be distinguished. Critical factors influencing FPR2 recognition comprise the presence of beta-peptoid phenylalanine-like residues (i.e., beta NPhe, beta Nspe, or beta Nrpe) 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 beta Nrpe residue in the vicinity of the N-terminus (i.e., Lau-[(S)-Aoc]-Lys-beta Nrpe[Lys-beta NPhe](5)-NH2) proved to increase the agonist potency, whereas the beta Nspe-containing analogue was a weak FPR2-selective antagonist. Another subclass displaying potent agonism comprised analogues possessing two alpha-amino acids vicinal to the headgroup. The optimized FPR2-activating lipidated peptidomimetics exhibited biased signaling: PLC-PIP2-Ca2+ signaling was activated, but without recruitment of beta-arrestin or induction of chemotaxis. These FPR2-interacting compounds are considered to be useful tools in future studies of receptor-ligand interactions.

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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