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

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.