Peptidomimetics

Peptidomimetics are compounds designed to mimic the structure and biological activity of peptides while overcoming limitations of natural peptides, such as poor proteolytic stability and limited oral bioavailability. They achieve this by modifying the peptide backbone, side chains, or stereochemistry so that the resulting molecules retain affinity for biological targets but resist enzymatic degradation.

Common strategies include isosteric replacements of the amide bond (esters, thioesters, or reduced/non-planar linkages), non-amide linkages such as carbamates or ureas, and backbone alterations such as beta- or gamma-amino acids. Peptoids, or N-substituted glycine oligomers, replace the alpha carbon side-chain with an N-substituent. Retro-inverse peptides invert the order and chirality of the amino acids to enhance stability. Stapled peptides introduce hydrocarbon crosslinks to stabilize alpha-helical conformation. Non-peptide mimetics may mimic key hydrogen-bonding patterns or side-chain pharmacophores while lacking a peptide backbone.

Applications include drug discovery efforts to inhibit proteases, block protein–protein interactions, and serve as receptor ligands, with work across oncology, infectious disease, and metabolic disorders. Design and optimization balance potency with pharmacokinetic properties, aiming for improved oral bioavailability, tissue distribution, and resistance to proteolysis.

Challenges include maintaining target affinity and selectivity, synthetic complexity, potential immunogenicity, and variable ADME properties. Peptidomimetics remain a major area in medicinal chemistry because they offer a path to combining the specificity of peptides with more drug-like properties.