title: Biological activity of for-Met-Leu-Phe-OMe analogs: relevant substitutions specifically trigger killing mechanisms in human neutrophils.
abstract: Two analogs of the prototypical peptide for-Met-Leu-Phe-OMe (fMLP-OMe), for-Gln-Tyr-Phe-OMe (1) and for-Gln-Tyr-Tyr-OMe (2), carrying unusual hydrophilic residues, were synthesized in order to investigate whether they provoked specific biological responses, as well as intracellular calcium mobilization, in human neutrophils. Whereas neither compound stimulates chemotaxis, both are able to elicit lysosomal enzyme production. However compound 1 is able to trigger copious superoxide anion production while compound 2 only elicits minor superoxide anion production. In binding experiments on formylpeptide receptors, the newly synthesized compounds for-Gln-Tyr-Phe-OMe (1) and for-Gln-Tyr-Tyr-OMe (2) showed affinity values in the micromolar range. These derivatives demonstrate inability to find a positive contribute from single substitutions. A very important result of this research is the evidence of the ability of the formyl group alone to trigger the primary target of the human neutrophil activity, i.e. killing mechanisms, by activating the specific receptor conformation.
authors.affiliation: Department of Pharmaceutical Sciences, University of Ferrara, Via Fossato di Mortara 17/19, 44100 Ferrara, Italy. g5z@unife.it
authors.forename: Giorgio
authors.initials: G
authors.lastname: Cavicchioni
authors.forename: Anna
authors.initials: A
authors.lastname: Fraulini
authors.forename: Marianna
authors.initials: M
authors.lastname: Turchetti
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.forename: Sofia
authors.initials: S
authors.lastname: Falzarano
authors.forename: Barbara
authors.initials: B
authors.lastname: Pavan
authors.forename: Susanna
authors.initials: S
authors.lastname: Spisani
mesh_terms: D001667:Binding, Competitive; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D009113:Muramidase / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D011869:Radioligand Assay; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism
chemical_list: D013481:Superoxides; D009240:N-Formylmethionine Leucyl-Phenylalanine; C042932:formylmethionyl-leucyl-phenylalanine methyl ester; D009113:Muramidase