Modified chemotactic peptides: synthesis, crystal conformation, and activity of For‐Hse(Me)‐Leu‐Phe‐OMe

Abstract

The presence of the sulfur atom of the methionine side chain exerts significant effects at different levels on biochemical behavior of chemotactic N-formylpeptides. In order to acquire more information on this point, the synthesis, the conformation in the crystal, and the activity of For-Hse(Me)-Leu-Phe-OMe (2)--an oxygen analogue of For-Met-Leu-Phe-OMe (fMLP-OMe) containing the O-methyl-L-homoserine in place of the native methionine at position 1--is reported. The new analogue 2 adopts a conformation that is extended at the first two residues and folded at the C-terminal phenylalanine. This conformation is different from that of the parent fMLP-OMe and strikingly similar to that adopted by fMLP-OBu(t). The side-chain spatial orientation of 2 corresponds to that adopted by fMLP-OH when cocrystallized with an immunoglobulin possessing binding properties similar to those of neutrophil receptors. When tested on human neutrophils the formylpeptide 2 is more active than the parent in the stimulation of directed mobility and maintains both the granule enzyme release activity and the superoxide anion production.

Conformational investigations on analogs of inflammation response inducing chemotactic tripeptide fMLP

“…To probe the structural requirement, these groups were mutated with residues having different steric, charge, and hydrophobic groups, and constraints were introduced to achieve the desired conformation. A large number of analogs of fMLP have been designed and synthesized, examined for their biological activities, and quite a few have also been studied for their conformation using X‐ray crystallography and NMR techniques 2, 9–22, 52–95. Results of conformational and activity studies on these peptides are summarized in Table V.…”

fMLP-OMe Analogs Substituted at the Methionine Residue: An Insight into the Receptor Properties

“…Indeed, when amino acids carrying linear or branched aliphatic side chains are inserted at position 1, a more or less marked loss of biological responses is evidenced [3] . Other substitutions showed discordant behaviour [4][5][6][7] .…”

The Importance of the Methionine Configuration in for-Met-Leu-Phe-OMe Biological Activities

“…It has been ascertained that the side chain of the residue at position 1 penetrates in a hydrophobic pocket of limited depth and capacity. A positively charged area has been proposed that surrounds the electron-rich sulphur atom, which in turn must be in a well-defined precise position (5,8).…”