Studies on the structural requirenents for synthetic formyl peptide chenoattractants

Abstract

Seven small molecular weight new peptides related to the chemotactic peptide N-formylmethionyl-leucyl-phenylalanine (CHO-Met-Leu-PheOH) have been prepared by classical peptide synthesis. Compounds were prepared by classical peptide synthesis. Compounds were prepared to evaluate the requirements at the C-terminal Phe group. Each analogue tested for its ability to induce lysosomal enzyme release from human neutrophils. The following new derivative of CHO-Met-Leu-Phe-R were prepared, where R is ▪ Chemotactic peptides have generated considerable interest in recent years. These peptides are of particular importance because they represent a mean of studying cellular immune responses using a defined pure material in contrast to ill-defined chemotactic factors of unknown composition (Wilkinson .1974) . Since Showell et al. (1976) have shown that N -formyl tripeptides are chemotactic towards rabbit peritoneal polymorphonuclear leucocytes, numerous structure-activity studies have been undertaken, in order to investigate the structural requirements for maximum pharmalogical activity of chemotactic peptides related to the standard chemotactic peptide N-formyl-methionyl-phenylalanine (FMLP). From these studies, five structural requirements for optimal activity of chemotactic peptides have been delineated. The N -formyl group is essential for good activity (Freer . 1980), the sulfur-containing side chain of position 1 methionine produces optimum activity of the tripeptide (Freer. 1980), the leucine side chain appears to be less restricted than for the methionine side chain however the branching at the carbon may be of importance (Freer . 1982), the phenylalanine side chain resides in an hydrophobic pocket of limited depth since para-substitutions on the phenylalanine ring markedly reduce biological activity (Wilkinson. 1974) (Day . 1977), the carbonyl function of the Phe residue seems to be required for good biological activity. Freer et al. (1982) proposed a critical interaction of the Phe C=0 with the receptor, possibly via hydrogen bonding. This final point appears to be less clear that the understanding of other structural requirements. Indeed, in 1978, Ho et al. reported that the methyl ester of CHO-Met-Leu-Phe-OH is more active in stimulating macrophage chemotaxis than the parent carboxylic compound, although it is less active against neutrophils. Morever addition of a lysine residue (i.e. CHO-Met-leu-Phe-Lys-OH) has relatively little effect on the biological activity against rabbit neutrophils (Freer . 1980). More recently, Freer et al. (1982) showed that the analogue in which the carboxyl group of the Phe residue was eliminated was only slightly active whereas the benzylamide and benzyl ester of CHO-Met-Leu-Phe-OH are even more potent than the parent compound. In order to provide new informations about the role of the phenylalanine carbonyl residue, we have undertaken a classical synthesis of new peptides, and the purpose of this comunication is to describe our results on the potency of these new peptides on the induction of lysosomal enzyme release from human leucocytes.