Conformational investigations on analogs of inflammation response inducing chemotactic tripeptide fMLP

Abstract

Conformations of three analogs of for-L-Met-L-Leu-L-Phe-OH (fMLP), which initiates inflammatory response by interaction with the formyl peptide receptor (FPR), have been investigated by the application of the X-ray crystallographic technique. The investigated analogs of fMLP peptides are as follows: for-L-Met-1-amino-1-cyclooctane-carbonyl(Ac8c)-L-Phe-OMe; for-L-Met-L-Leu-L-p-iodo-Phe-OH; and for-L-Met-di-n-propylglycyl(Dpg)-L-Phe-OMe. The peptide backbone in and is constrained at position of fMLP by the introduction of Calpha,alpha-disubstituted glycines. In peptide, Phe-OMe is substituted by p-iodo-Phe-OH. Crystal structures reveal an overall folded conformation adopted by and. The former is folded in the type II beta-turn, which is stabilized by an intramolecular 1<--4 (formyl) C==O...H--N (Phe) hydrogen bond, whereas the latter is folded in an open turn without any intramolecular hydrogen bond. On the other hand, peptide has an extended conformation, and two different molecules in a crystallographic asymmetric unit form an antiparallel beta-sheet-like structure. In and, residues Ac8c and Dpg adopt left-handed helical and fully extended (C5) conformations, respectively. The cyclooctane ring in Ac8c acquires a boat-chair conformation. Crystal packing of is characterized by the association of aliphatic-aromatic rings via a C--H...pi interaction. In the crystal of, contrary to the usual observations, peptides are interlinked via networks of head-to-tail hydrogen bond and pi...pi interactions, which are generally observed to be mutually exclusive. The structure-function mechanism of the ligand-receptor interaction is discussed.

Structural Requirements for Molecular Recognition by fMLP Analogs Receptors: Comparative Conformational Analysis of (for-Met-Leu-Phe-OMe) and its Thioamide Analog (for-Met-Leuψ[CSNH]Phe-OMe)

“…It is worth noting that several authors have suggested this structure for many fMLP-OMe analogs, using spectroscopic X-ray and NMR methods as well as molecular modeling studies. 21,23-25,38-42. Fig.4a shows a stereoscopic view of the superposition of our β turn structure (conformer 2, table 1) with those found by Bardi for the Boc-Met-Aib-Phe-OMe analog 21 , Rathore for the f-Met-AC8C-Phe-OMe 38 and Zecchini for the f-Met-Δ Z Leu-Phe-OMe 39 . This figure shows that there is a great similarity at the backbone level and that the only differences with our structure lie just at the side chains orientation of Methionine and Phenylalanine.…”

Synthesis and biological evaluation of new active For‐Met‐Leu‐Phe‐OMe analogues containing para‐substituted Phe residues

“…Relevant and extensively studied among these functions are the catalyzed conversion of molecular oxygen to superoxide anion (O 2 − ) (respiratory burst) and the release of lysosomal enzymes. However, because of the complexity of the intracellular signaling pathways and the peculiar characteristics of the involved receptors, which are rapidly desensitized and internalized soon after the interaction with the ligand, several aspects concerning the involved biochemical mechanisms and the structure–activity relationships concerning N ‐formylpeptides are still scarcely understood and continue to be the object of active investigation .…”

“…Since the Schiffmann original discovery of the chemoattractant activity of N ‐formylpeptides , the tripeptide fMLF and its methyl ester For‐Met‐Leu‐Phe‐OMe (fMLF‐OMe) have been adopted as reference model for structure–activity relationships and conformational studies . Great attention has been dedicated to the role exerted by the N ‐formyl group and the Met residue at the first position.…”