A highly active chemotactic peptide analog incorporating the unusual residue 1-aminocyclohexanecarboxylic acid at position 2

Abstract

Analogs of chemotactic peptides (Formyl-Met-X-Phe-OMe) containing the stereochemically constrained residues α-aminoisobutyric acid (Aib), 1-aminocyclopentanecarboxylic acid (Acc⁵) and 1-aminocyclohexanecarboxylic acid (Acc⁶) at position 2 are compared with the parent sequence (X = Leu) for their ability to induce lysozyme release in rabbit neutrophils. The Acc⁶ analog is about 78 times more active than the parent peptide, For-Met-Leu-Phe-OH, whereas Aib and Acc⁵ analogs are approximately 3 and 2 times, respectively, less active than the parent peptide. NMR and model building studies clearly favour a Met-Acc⁶β-turn solution conformation in the Acc6 analog, suggesting that the neutrophil receptor is capable of recognizing a folded peptide structure. The significant differences in the activities of the Acc⁵ and Acc⁶ analogs suggest an important role for the residue 2 sidechain in receptor interactions. Accⁿ, 1-aminocycloalkanecarboxylic acid residue, where n is the number of atoms in the cycloalkane ring; Aib, α-amino-isobutyric acid; Boc, t-butyloxycarbonyl; For, formyl; TEMPO, 2, 2, 6, 6-tetramethyl-piperidine-1-oxyl.