Construction and cytotoxicity evaluation of peptide nanocarriers based on coiled-coil structures with a cyclic β-amino acid at the knob-into-hole interaction site†

Peptides are highly attractive as nanocarriers for drug delivery and other biomedical applications due to their unique combination of biocompatibility, efficacy, safety, and versatility—qualities that are difficult to achieve with other nanocarrier types. Particularly promising in this context are peptide foldamers containing non-canonical residues, which can yield nanostructures with diverse physicochemical properties. Additionally, the introduction of non-proteinogenic amino acids into the sequence enhances conformational stability and resistance to proteolysis, critical features for bioapplications. In this article, we report the development of novel foldameric bundles based on a coiled-coil structure incorporating trans-(1S,2S)-2-aminocyclopentanecarboxylic acid (trans-ACPC) at the key interacting site. We also provide both theoretical and experimental analyses of how this cyclic β-residue affects the thermodynamic and proteolytic stability, oligomerization state, and encapsulation properties of the resulting foldamers compared to standard coiled-coils. Additionally, we assessed the cytotoxicity of these foldamers using the MTT assay on 3T3 cells. The results demonstrate that neither the foldamers nor trans-ACPC exhibit toxic effects on the 3T3 cell line, highlighting their potential as safe and effective nanocarriers.