Heterochiral homo-oligomers with alternating backbone configurations were constructed by using the different enantiomers of the cis- and trans-2-aminocyclopentanecarboxylic acid (ACPC) monomers. Molecular modeling and the spectroscopic techniques (NMR, ECD, and VCD) unequivocally proved that the alternating heterochiral cis-ACPC sequences form an H10/12 helix, where extra stabilization can be achieved via the cyclic side chains. The ECD and TEM measurements, together with molecular modeling, revealed that the alternating heterochiral trans-ACPC oligomers tend to attain a polar-strand secondary structure in solution, which can self-assemble into nanostructured fibrils. The observations indicate that coverage of all the possible secondary structures (various helix types and strand-mimicking conformations) can be attained with the help of cyclic beta-amino acid diastereomers. A relationship has been established between the backbone chirality pattern and the prevailing secondary structure, which underlines the role of stereochemical control in the beta-peptide secondary structure design and may contribute to future biological applications.

Endomorphins were subjected to a number of structural modifications in a search for their bioactive conformations. The alicyclic β-amino acids cis-(1S,2R)ACPC/ACHC, cis-(1R,2S)ACPC/ACHC, trans-(1S,2S)ACPC/ACHC, and trans-(1R,2R)ACPC/ACHC were introduced into endomorphins to examine the conformational effects on the bioactivity. Use of a combination of receptor binding techniques, 1 H NMR, and molecular modeling allowed the conclusion that Pro 2 substitution by these residues causes changes in structure, proteolytic stability, and pharmacological activity. It seems that the size of the alicyclic β-amino acids does not have marked influence on the receptor binding affinities and/or selectivities. Among the new analogues, the cis-(1S,2R)ACPC 2 and cis-(1S,2R)ACHC 2 -containing derivatives displayed the highest binding potencies and efficacies in receptor binding and ligand-stimulated [ 35 S]GTPγS functional experiments. Molecular dynamic simulations and 1 H NMR studies of the cis-ACPC/ACHC-containing analogues revealed that many conformations are accessible, though it is most likely that these peptides bind to the µ-opioid receptor in a compact, folded structure rather than extended.