Peptide homologs, isosteres, and isomers: A general approach to structure–activity relationships

A general approach to study peptide structure is presented using three areas of ongoing research in our laboratories. The first involves the molecular basis for taste of peptide derivatives. We synthesized dipeptides based on L ‐aspartyl‐α‐aminocycloalkane carboxylic acid methyl ester. A homologous series of cycloalkane derivatives was studied. The cyclopropane, cyclobutane, and cyclopentane derivatives are sweet, the cyclohexane and cycloheptane peptides are bitter, and the cyclooctane homolog is tasteless. The related acyclic analog L ‐aspartyl‐aminoisobutyric acid methyl ester is sweet, while the L ‐aspartyl diethyl glycine carboxylic acid methyl ester is tasteless. A model is presented to explain these experimental observations. The second area involves depsipeptides as isosteric replacements of α‐hydroxy acids for amino acid residues in peptide chains. We have synthesized sequentially defined polydepsipeptides as model systems for polypeptides. A detailed analysis of the conformational order for these polydepsipeptides is presented. The third area involves partial retro–inverso peptide modifications of isomeric cyclic enkephalin analogs, which illustrate the relationship between the modification and biological activity. We are probing the intramolecular hydrogen‐bonding features for these biologically active molecules. From such findings we are relating the structural and conformational preferences deduced from spectroscopy and molecular mechanics to biological activity.