peptidomimetic

Peptidomimetics are chemical compounds that reproduce the functional properties of peptides while possessing modified backbones or nonnatural components that enhance stability, bioavailability, or selectivity. They are designed to mimic the physicochemical features of peptide ligands, such as hydrogen-bonding patterns and side-chain topology, but aim to resist proteolysis and improve pharmacokinetic properties.

Design approaches include substituting the peptide bond with isosteres (for example hydroxyethylene, thioamide, or other amide bond surrogates), incorporating non-natural amino acids (D- or L-enantiomers, beta-amino acids), building peptoids (N-substituted glycine polymers), retro-inverso peptides, and imposing conformational constraints through cyclization or bulky scaffolds. Other strategies involve non-peptide scaffolds that present the same arrangement of side chains as a given peptide ligand.

These modifications can confer resistance to proteolytic enzymes, improve oral bioavailability, extend half-life, and enhance receptor selectivity. However, challenges include more complex synthesis, potential alterations in activity, and higher development costs or immunogenicity concerns.

Peptidomimetics are widely used in drug discovery and chemical biology as enzyme inhibitors, receptor modulators, and antimicrobial agents. Well-known classes include hydroxyethylene isosteres in HIV protease inhibitors and ACE inhibitors; peptoids and beta-peptides are explored as protease-resistant mimics of natural peptides. They also serve as tools for studying peptide-receptor interactions and as diagnostic probes.