An evaluation of fMLP pocket dimensions and features using formyltetrapeptides

Abstract

The formyltetrapeptides for-Met-Leu-Leu-Phe-OMe 1, for-Met-Leu-Aib-Phe-OMe 2, for-Met-Leu-Ac6c-Phe-OMe 3, for-Met-Leu-Pro-Phe-OMe 4, for-Met-Pro-Pro-Phe-OMe 5, for-Met-Aib-Aib-Phe-OMe 6, for-Met-Pro-Aib-Phe-OMe 7 and for-Met-Aib-Pro-Phe-OMe 8 were synthesized and biologically tested on human neutrophils in an attempt to evaluate the specific receptor pocket dimensions and features. Our results indicate that the shift in the Phe residue to the fourth position in these compounds strongly reduces chemotactic response, but is efficacious in triggering superoxide anion production and lysozyme release (order of potency 3 > 2 > 1 > 4 > 6 > 8 > 5 > 7). The potency of the two latter responses correlates well with the affinity data obtained in binding experiments.

Differences Arising in Human Neutrophil Activation Passing from N-Formyl to N-Acetyl-oligopeptides

“…Our results agree with both our previous studies (14,15) and present knowledge of the features of the amino-terminal pocket (7,16).…”

Conformational investigations on analogs of inflammation response inducing chemotactic tripeptide fMLP

“…The retroisomer of fMLP, i.e., CHO–Phe–Leu–Met–NH 2 and its D analogs were found to be 100 to 10,000 times less active 74. Many other formyl peptides were also examined recently, for biological activities;75–95…”

“…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.…”

Biological variation responses in fMLP‐OMe analogs, introducing bulky protecting groups on the side‐chain of hydrophilic residues at position 2

“…On the basis of these findings, we thought it would be interesting to study the effect of introducing a hydrophilic residue at position 2 (16). Interesting results were obtained, which stressed the understimulation of chemotaxis together with the strong elicitation of killing mechanisms (i.e.superoxide anion production and lysosomal enzyme release).…”

“…These compounds were characterized and their biological activity on human neutrophils was evaluated. Moreover, the activities of the new compounds were compared with those of the analogs with unprotected side‐chains at position 2 (16).…”