An enzyme that cuts a peptide chain in the middle rather than nibbling from the ends—often the first step in peptide degradation.Endopeptidases cleave internal peptide bonds, distinguishing them from exopeptidases that remove terminal residues. Major endopeptidases relevant to peptide therapeutics include neprilysin (NEP/CD10), endothelin-converting enzyme (ECE), insulin-degrading enzyme (IDE), and matrix metalloproteinases (MMPs). Endopeptidase-mediated degradation is the primary mechanism limiting the plasma half-life of most linear peptides. Drug design strategies to resist endopeptidase cleavage include cyclization, D-amino acid substitution at cleavage sites, and backbone modifications.