Structural requirements for formyl homooligopeptide chemoattractants

Abstract

Using solution peptide synthesis, 3 series of N.alpha.-formylated homooligopeptides were made from the dipeptide to the heptapeptide, derived from L-methionine, L-norleucine, and S-methyl-L-cysteine and related to the chemotactic peptide N.alpha.-formylmethionylleucylphenylalanine. Compounds were prepared to determine the combined effects of the main-chain length and the presence of a sulfur atom in side-chain .gamma.- and .delta.-positions. Each peptide was tested for its ability to induce rabbit peritoneal polymorphonuclear leukocytes in the presence of cytochalasin B to secrete granule enzymes. In parallel, a conformational analysis was carried out in the solid state and in solution, using infrared absorption and circular dichroism. These peptides were examined in solvents of widely different polarities, i.e., chloroform, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoropropan-2-ol, and mixed organic-aqueous media. The tendencies to form antiparallel-chain .beta.-associated and folded structures were determined. The biological and conformational data are described in terms of a model of the chemotactic peptide receptor of rabbit neutrophils. In the 3 N.alpha.-formylated C-methoxy homooligopeptide series tested, the highest level of activity attained is at the tetrapeptide or pentapeptide stage, confirming the suggestion that the formylpeptide receptor is large enough to accommodate a peptide with at least 4 amino acid residues. All 3 homooligopeptide series, starting at the tetrapeptide, show a high propensity to give self-associated .beta.-structures (certainly at least in part of the antiparallel type) in a solvent of low polarity (CDCl3) which can mimic the environment at the receptor site. This could be the biologically active conformation of the ligand.