title: Development of potent antagonists for formyl peptide receptor 1 based on Boc-Phe-D-Leu-Phe-D-Leu-Phe-OH.
abstract: While stimulation of formyl peptide receptors (FPRs) on the surface of human neutrophils induces several immune responses, under conditions of continuous activation of the receptor by agonists such as formyl-Met-Leu-Phe-OH (fMLP), neutrophil-dependent tissue damage ensues. Thus, FPR antagonists could be anticipated as drugs for FPR-related disease. In this study, Boc-Phe-D-Leu-Phe-D-Leu-Phe-OH (Boc-FlFlF), one of several FPR subtype selective antagonists, was chosen and the positions at the Phe residues were optimized. We found that substitution with unnatural amino acids resulted in an improvement of two orders of magnitude. The most potent antagonist indicated FPR subtype selectivity at 1 μM. In addition to finding a potent antagonist, the structure-activity trends observed in this study should be valuable in designing a new type of FPR subtype selective antagonist.
authors.affiliation: Department of Chemistry, Graduate School of Science and Engineering, Saga University, 1 Honjo-machi, Saga 840-8502, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Hayashi
authors.affiliation: Department of Chemistry, Graduate School of Science and Engineering, Saga University, 1 Honjo-machi, Saga 840-8502, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Kitajima
authors.affiliation: Department of Chemistry, Graduate School of Science and Engineering, Saga University, 1 Honjo-machi, Saga 840-8502, Japan.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Mizuguchi
authors.affiliation: Department of Chemistry, Graduate School of Science and Engineering, Saga University, 1 Honjo-machi, Saga 840-8502, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Fujimoto
authors.affiliation: Department of Chemistry, Graduate School of Science and Engineering, Saga University, 1 Honjo-machi, Saga 840-8502, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Yamaguchi
authors.affiliation: Department of Chemistry, Graduate School of Science and Engineering, Saga University, 1 Honjo-machi, Saga 840-8502, Japan.
authors.forename: Shuichiro
authors.initials: S
authors.lastname: Koga
authors.affiliation: Department of Chemistry, Graduate School of Science and Engineering, Saga University, 1 Honjo-machi, Saga 840-8502, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Koga
authors.affiliation: Department of Chemistry, Graduate School of Science and Engineering, Saga University, 1 Honjo-machi, Saga 840-8502, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Osada
authors.affiliation: Department of Chemistry, Graduate School of Science and Engineering, Saga University, 1 Honjo-machi, Saga 840-8502, Japan. Electronic address: hiroaki@cc.saga-u.ac.jp.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kodama
mesh_terms: D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D044042:Receptors, Formyl Peptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D009842:Oligopeptides; D044042:Receptors, Formyl Peptide; C081709:tert-butyloxycarbonyl-phenylalanyl-leucyl-phenylalanyl-leucyl-phenylalanyl-OH; D002118:Calcium
keywords: Boc-FlFlF-OH; Formyl peptide receptor; Selective antagonist