title: Design, synthesis and characterization of fMLF-mimicking AApeptides.
abstract: The tripeptide N-formyl-Met-Leu-Phe (fMLF) is a potent neutrophil chemoattractant and the reference agonist for the G protein-coupled N-formylpeptide receptor (FPR). As it plays a very important role in host defense and inflammation, there has been considerable interest in the development of fMLF analogues in the hope of identifying potential therapeutic agents. Herein we report the design, synthesis, and evaluation of AApeptides that mimic the structure and function of fMLF. The lead AApeptides induced calcium mobilization and mitogen-activated protein kinase (MAPK) signal transduction pathways in FPR-transfected rat basophilic leukemic (RBL) cells. More intriguingly, at high concentrations, certain AApeptides were more effective than fMLF in the induction of calcium mobilization. Their agonistic activity is further supported by their ability to stimulate chemotaxis and the production of superoxide in HL-60 cells. Similarly to fMLF, these AApeptides are much more selective towards FPR1 than FPR2. These results suggest that the fMLF-mimicking AApeptides might emerge as a new class of therapeutic agents that target FPRs.
authors.affiliation: Department of Chemistry, University of South Florida, 4202 E. Fowler Avenue, Tampa, FL 33620 (USA).
authors.forename: Yaogang
authors.initials: Y
authors.lastname: Hu
authors.forename: Ni
authors.initials: N
authors.lastname: Cheng
authors.forename: Haifan
authors.initials: H
authors.lastname: Wu
authors.forename: Samuel
authors.initials: S
authors.lastname: Kang
authors.forename: Richard D
authors.initials: RD
authors.lastname: Ye
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Cai
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002633:Chemotaxis; D018922:HL-60 Cells; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry; D009504:Neutrophils / Q000201:enzymology; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D044042:Receptors, Formyl Peptide / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D044067:Receptors, Lipoxin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014162:Transfection
chemical_list: C469986:FPR1 protein, human; C105101:FPR2 protein, human; D057786:Peptidomimetics; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D013481:Superoxides; D009240:N-Formylmethionine Leucyl-Phenylalanine; C042205:methionyl-leucyl-phenylalanine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium
keywords: AApeptides; calcium; chemotaxis; fMLF; peptidomimetics