Combining Elements from Two Antagonists of Formyl Peptide Receptor 2 Generates More Potent Peptidomimetic Antagonists.

Structural optimization of a peptidomimetic antagonist of formyl peptide receptor 2 (FPR2) was explored by an approach involving combination of elements from the two most potent FPR2 antagonists described: a Rhodamine B-conjugated 10-residue gelsonin-derived peptide (i.e., PBP, RhB-QRLFQVKGRR-OH) and the palmitoylated α-peptide/β-peptoid hybrid Pam-(Lys-βNspe)-NH. This generated an array of hybrid compounds from which a new subclass of receptor-selective antagonists was identified. The most potent representatives displayed activity in the low nanomolar range. The resulting stable and potent FPR2-selective antagonists (i.e., RhB-(Lys-βNphe)-NH; n = 4-6) are expected to become valuable tools in further elucidation of the physiological role of FPR2 in health and disease.