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-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 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-NH2) 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-PIP2-Ca2+ 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.

甲酰肽受体2（Formyl peptide receptor 2, FPR2）在炎症反应中发挥重要作用。本研究中，我们合成了20种FPR2选择性脂化α肽/β类肽（α-peptide/β-peptoid）激动剂Lau-[(S)-Aoc]-[Lys-βNPhe]6-NH2的类似物，借此得以区分两类新型且活性更强的FPR2激动剂亚类。影响FPR2识别的关键因素包括：拟肽尾段中含类苯丙氨酸β类肽残基（即βNPhe、βNspe或βNrpe）、头部基团中2-氨基辛酸（2-aminooctanoic acid, Aoc）的构型，以及N端脂肪酸的链长。有趣的是，在N端附近引入单个βNrpe残基的类似物（即Lau-[(S)-Aoc]-Lys-βNrpe-[Lys-βNPhe]5-NH2）可提升激动剂活性，而含有βNspe的类似物则是一种弱选择性FPR2拮抗剂。另一类显示出强效激动活性的亚类，则包含头部基团附近带有两个α氨基酸的类似物。经优化的FPR2激活型脂化拟肽类化合物展现出偏倚信号转导特性：其可激活PLC-PIP2-Ca2+信号通路，但不会招募β抑制蛋白（β-arrestin）或诱导趋化反应（chemotaxis）。这些可与FPR2结合的化合物，有望成为未来受体-配体相互作用研究中的实用工具。