Premium
Synthesis, conformation, and activity of HCO‐Met‐Δ Z Leu‐Phe‐Ome, an active analogue of chemotactic N ‐formyltripeptides
Author(s) -
Pagani Zecchini G.,
Paradisi M. Paglialunga,
Torrini I.,
Lucente G.,
Gavuzzo E.,
Mazza F.,
Pochetti G.,
Paci M.,
Sette M.,
Di Nola A.,
Veglia G.,
Traniello S.,
Spisani S.
Publication year - 1993
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.360330310
Subject(s) - chemistry , tripeptide , stereochemistry , residue (chemistry) , intramolecular force , chemotaxis , phenylalanine , peptide , circular dichroism , superoxide , tetrapeptide , enzyme , amino acid , biochemistry , receptor
Abstract In order to induce a β‐turn conformation into the chemotactic linear tripeptide N ‐formyl‐ L ‐methionyl‐ L ‐leucyl‐ L ‐phenylalanine (fMLP), the new analogue N ‐formyl‐ L ‐methionyl‐Δ Z leucyl‐ L ‐phenylalanine methyl ester [ Δ Z Leu] 2 f MLP‐OMe ( 1 ) has been synthesized. The conformational and biochemical consequences of this chemical modification have been determined. Analogue 1 has been synthesized by using N ‐carboxy‐(Z)‐α,β‐didehydroleucine anhydride as key compound to introduce the unsaturated residue at the central position of the tripeptide 1 . The x‐ray analysis shows that 1 adopts in the crystal a type II β‐turn conformation in which the new residue occupies the ( i + 2) position, and an intramolecular H bond is formed between the formylic oxygen and the Phe NH. 1 H‐nmr analysis based on nuclear Overhauser effect measurements suggests that the same folded conformation is preferred in CDCl 3 solution; this finding is also supported by molecular dynamics simulation. The biological activity of 1 has been determined on human neutrophils (polymorphonuclear leukocytes) and compared to that shown by f MLP‐OMe. Chemotactic activity, granule enzyme release, and superoxide anion production have been determined. Analogue 1 is practically inactive as chemoattractant, highly active in the superoxide generation, and similar to the parent in the lysozyme release. The conformational restriction imposed on the backbone by the presence of the unsaturated residue is discussed in relation with the observed bioselectivity. © 1993 John Wiley & Sons, Inc.