title: Discovery of Trp-Nle-Tyr-Met as a novel agonist for human formyl peptide receptor-like 1.
abstract: Formyl peptide receptor-like 1 (FPRL1) is a structural homologue of FPR, which binds chemotactic peptides as small as three amino acids (e.g., fMet-Leu-Phe, fMLF) and activates potent bactericidal functions in neutrophils. In comparison, FPRL1 ligands include peptides of 6-104 amino acids, such as Trp-Lys-Tyr-Met-Val-[d]Met (WKYMVm) and other synthetic peptides. To determine the core peptide sequence required for FPRL1 activation, we prepared various analogues based on WKYMVm and evaluated their bioactivities in an FPRL1-transfected cell line. Although substitution of d-Met(6) resulted in loss of activity, removal of Val(5) together with d-Met(6) produced a peptide that retained most of the bioactivities of the parent peptide. The resulting peptide, WKYM, represents a core structure for an FPRL1 ligand. Further substitution of Lys(2) with Nle slightly improved the potency of the tetrapeptide, which selectively activates FPRL1 over FPR. Based on these structure-activity relationship studies, we propose a model in which the modified tetrapeptide Trp-Nle-Tyr-Met (WNleYM) binds to FPRL1 through aromatic interactions involving the side chains of Trp(1) and Tyr(3), hydrophobic interaction of Nle(2), and the thio-based hydrogen bonding of Met(4), with the respective residues in FPRL1 which have not been identified. The identification of the core sequence of a potent peptide agonist provides a structural basis for future design of peptidomimetics as potential therapeutic agents for FPRL1-related disorders.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Hui-Xin
authors.initials: HX
authors.lastname: Wan
authors.forename: Caihong
authors.initials: C
authors.lastname: Zhou
authors.forename: Yueyun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Meiling
authors.initials: M
authors.lastname: Sun
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Yang
authors.forename: Richard D
authors.initials: RD
authors.lastname: Ye
authors.forename: Jing-Kang
authors.initials: JK
authors.lastname: Shen
authors.forename: Ming-Wei
authors.initials: MW
authors.lastname: Wang
mesh_terms: D002630:Chemotactic Factors / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology*; D044042:Receptors, Formyl Peptide / Q000819:agonists* / Q000502:physiology; D044067:Receptors, Lipoxin / Q000819:agonists* / Q000502:physiology; D013329:Structure-Activity Relationship; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
chemical_list: D002630:Chemotactic Factors; C105101:FPR2 protein, human; D009842:Oligopeptides; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C113617:Trp-Lys-Tyr-Met-Val-Met; C521868:tryptophyl-norleucyl-tyrosyl-methionine; D001619:beta-N-Acetylhexosaminidases