Table 2.

Principal strategies to enhance the proteolytic stability of AMPs.

Terminal modification	N-acylation, C-amidation, formation of N-pyroglutamate and carbohydrate, PEGylation, sialyation.
Cyclization	Head-to-tail cyclization, head-to-side-chain cyclization, side-chain-to-side-chain cyclization (e.g., disulphide and lanthionine bridge formation).
Replacement of one or more residues with non-proteinogenic amino acid	D-amino acids, N-methyl-α-amino acids, proteinogenic amino acid derivatives with a rigid structure (e.g., Spi, Tic), β-amino acids, γ-amino acids, α-substituted amino acids, β-substituted α-amino acids, proline analogues.
Formation of pseudopetides (replacing peptide bonds with other chemical groups)	N-alkylation, carbonyl function substitution with a methylene group, carbonyl-O substitution with a sulfur atom or phosphonamide, NH group substitution with oxygen (depsipeptide), sulfur (thioester) or methylen (ketomethylene). Introduction of a retro-inverso peptide bond, methylene or thiomethylene bond, a –CH2–CH2– bond, or a hydroxyethylene bond. Formation of azapeptides, peptoids and dehydropeptides.
Elimination of one or more residues	Deletion of amino acid residues which are more susceptible to proteolytic attack.
Prodrug approach	Introduction of a labile modification, maintaining the peptide structure almost unchanged by means of peptide conjugation with a polymer.
Use of protease inhibitors	Co-administration of the peptide and a specific enzyme inhibitor.
Formulation modification	Application of specific drug carriers (liposomes, ethosomes, transferosomes, cubosomes, nanostructured lipid carriers, solid lipid nanoparticles, biopolymers).