title: New chemotactic dimeric peptides show high affinity and potency at the human formylpeptide receptor.
abstract: A number of analogues of the prototypical peptide for-Met-Leu-Phe-OMe (fMLP-OMe) have been studied in order to evaluate their ability to interact with formylpeptide receptors and to induce specific biological responses in human neutrophils. In vitro assays were carried out and receptor binding, chemotaxis, superoxide anion release and secretagogue activity were evaluated. The fMLP-OMe analogues synthesized, with the general formula for-Met-Leu-Phe-Xaa-Lys(OMe)-Phe-Leu-Met-for (Xaa=Gly, beta-Ala, gamma-aminobutyric acid, 5-aminovaleric acid, and 6-aminocaproic acid), were constituted by two fMLP units linked by a Lys residue, with an amino acid spacer between them. Competition binding experiments revealed that the new compounds have much more affinity for formylpeptide receptors than the reference ligand, with good correlation between receptor affinity and length of spacer. The EC(50) values for the killing mechanisms of each analogue were similar to each other, the affinity and potency, once again, being strictly dependent on the chain length. Furthermore the analogues proved to be more potent full agonists than the prototype fMLP-OMe in these functions, while chemotaxis was poorly induced. The dimeric fMLP-OMe analogues are one of the few examples of formylpeptides which exhibit a receptor affinity greater than the parent fMLP-OMe thereby rendering them suitable to be used as carriers for various drugs.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ferrara, 44100 Ferrara, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Spisani
authors.forename: Anna
authors.initials: A
authors.lastname: Fraulini
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.forename: Sofia
authors.initials: S
authors.lastname: Falzarano
authors.forename: Giorgio
authors.initials: G
authors.lastname: Cavicchioni
mesh_terms: D021542:Amino Acids, Neutral / Q000737:chemistry; D015119:Aminocaproic Acid / Q000737:chemistry; D001667:Binding, Competitive; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D019281:Dimerization; D006801:Humans; D066298:In Vitro Techniques; D008247:Lysosomes / Q000201:enzymology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D011869:Radioligand Assay; D044042:Receptors, Formyl Peptide / Q000819:agonists*; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000737:chemistry
chemical_list: D021542:Amino Acids, Neutral; D044042:Receptors, Formyl Peptide; D013481:Superoxides; D005680:gamma-Aminobutyric Acid; D009240:N-Formylmethionine Leucyl-Phenylalanine; C042932:formylmethionyl-leucyl-phenylalanine methyl ester; C013809:5-aminovaleric acid; D015119:Aminocaproic Acid