Structure activity relationship involving chemotactic peptide analog models

Chemotaxis is defined as the ability of a cell to move towards a stimulus. Chemoattractants such as formyl peptides promote chemotaxis of neutrophils. As a result of the ligand-receptor interaction between the formyl peptide and the neutrophil, formyl peptides find an application in the medical field in the area of lesion detection. Formyl peptides have an advantage of being small compared to other agents used for lesion detection.

The aim of this study is to successfully design a peptide which is small and shows high chemotactic activity. To achieve this goal, it is important that the effect of conformation of the peptide on the peptide-receptor interaction be well understood.

For this purpose, analogs of the chemotactically active dipeptide, f-Met-Leu namely f-Gly-Leu-OMe, f-Ala-Leu-OMe, f-Aib-Leu-OMe, f-Cpp-Leu-OMe and f-Cyp-Leu-OMe were synthesized and their conformation and biological activity studied.

The conformation of the peptides at 20 mM peptide concentration has been deduced using the results obtained from NMR and IR experiments. The peptides f-Gly-Leu-OMe and f-Ala-Leu-OMe exist as an equilibrium between the various intermolecularly and intramolecularly hydrogen bonded conformers. The major conformer for f-Aib-Leu-OMe, f-Cpp-Leu-OMe, and f-Cyp-Leu-OMe is one that has an elaborate network of intra- and intermolecular hydrogen bonds. The leucine NH proton in all the three peptides is involved in an intramolecular hydrogen bond formation, while, the Aib NH proton in the peptide f-Aib-Leu-OMe, the Cyp NH proton in the peptide f-Cyp-Leu-OMe and the Cpp NH proton of the peptide f-Cpp-Leu-OMe are involved in the formation of intermolecular hydrogen bonds.

Biological studies show that of all the five peptides, the peptide f-Aib-Leu-OMe is the most chemotactically active. The reasons for the higher chemotactic activity of the peptide f-Aib-Leu-OMe could be two-fold. The formyl carbonyl, the NH hydrogen and the carbonyl oxygen of the peptide f-Aib-Leu-OMe may be ideally spaced so that these groups have a very efficient interaction with the groups in the receptor site. The second reason may be that the formyl carbonyl and the two methyl groups in the peptide f-Aib-Leu-OMe are sufficiently far apart so that they fit exactly into the receptor pocket.