Importance of Secondary Structure Modifications
It is difficult for small molecules to target protein-protein interactions (PPIs) because the binding surfaces between proteins are often large, involve many polar and hydrophobic interactions, and most do not have a defined binding pocket to bind small molecules . Peptides can be designed from the native sequence in the protein that mediate PPI and increase the potency of action by inducing the desired secondary structure.
The secondary structural motifs involved in the PPI interface mainly include: α-helix, β-sheet and b-strand, peptidomimetics containing such motifs are designed to fix those biologically active conformations that are highly characterized by such structural elements, thereby effectively PPI analysis was performed.
Fig. 1 Chemical approaches for stabilizing peptidomimetics of alpha-helices. (Lenci, E., & Trabocchi, A., 2020)
Types of Secondary Structure Peptidomimetics
α-helices are the most common peptide secondary structure and can be stabilized by the use of unnatural amino acids, N-terminal capping, or side-chain linkers (stapling). The introduction of α-helix peptidomimetics not only achieves better stability, but also significantly improves cell permeability.
Fig. 2 Schematic diagram of α-helix.
β-Sheets are secondary structures composed of β-chains connected by a regular array of intramolecular hydrogen bonds. β-sheets, β-strands, and β-hairpins represent interesting structural elements for peptidomimetic development, especially in the field of central nervous system diseases, since β-sheets are involved in the formation of protein aggregates.
Fig. 3 Schematic diagram of β-Sheets.
β-Turns are irregular secondary structures characterized by non-repeating dihedral angles in their backbone, allowing the polypeptide chain to fold on itself. β-Turns play important roles in many biorecognition systems, for example in several peptide-antibody interactions, and in binding interactions between peptide ligands and proteins.
Fig. 4 Schematic diagram of β-Turns.
The combination of two antiparallel β-strands connected by a turn provides a β-hairpin that stabilizes the extended interchain hydrogen bonding pattern. Turn-inducing amino acids such as L-ornithine are privileged motifs for stabilizing β-hairpins.
Fig. 5 Schematic diagram of β-hairpin.