Proteolysis
The breakdown of peptides and proteins into smaller fragments or individual amino acids by enzymes called proteases. Proteolysis is the primary mechanism by which the body clears peptide drugs, and overcoming proteolytic degradation is a central challenge in peptide drug design.
Technical Context
Proteolysis occurs at multiple sites in the body: the gastrointestinal tract (pepsin, trypsin, chymotrypsin), blood plasma (various circulating proteases), liver, kidneys, and within cells (lysosomal proteases, proteasome). For peptide drugs, proteolysis determines half-life and dosing frequency. Strategies to resist proteolysis include: D-amino acid incorporation, N-terminal acetylation, C-terminal amidation, backbone modifications (N-methylation, reduced peptide bonds), cyclisation, PEGylation, lipidation for albumin binding, and formulation in sustained-release systems. The specific protease(s) responsible for degrading each therapeutic peptide are typically identified during preclinical development to guide stabilisation strategies.