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Coeliac disease is caused by an acquired immune response to proline\u2010 and glutamine\u2010rich gluten peptides, which bottleneck proteolysis and provide substrates for immune recognition. Enzyme therapies aim to eliminate gluten immunogenic peptides as an adjunct to gluten\u2010free diet.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aims<\/jats:title><jats:p>To investigate overlooked aspects of enzyme development given difficulties in translating preclinical efficacy into clinical benefit.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We assessed mode\u2010of\u2010action, target organ and drug delivery in the context of digestive physiology and motility for gluten\u2010digesting enzymes on the market or in development until 1 December 2024.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Most enzymes were gastric endopeptidases specific for proline or glutamine residues. Gastric enzymes may achieve poor enzyme\u2013substrate exposure due to limited mixing and rapid emptying of water\u2010soluble particles. Moreover, endopeptidases cleave proteins\/peptides into shorter peptides but do not systematically cleave protein into absorbable fractions. Natural digestive physiology provides thorough mixing at the intestinal brush border, which produces exopeptidases necessary to fully digest proline\u2010rich peptides. Despite reduced activity in patients with coeliac disease, exopeptidases remain underexplored as therapeutic agents. Given limited substrate scope and end\u2010to\u2010end digestion, exopeptidases are ineffective as single agents, requiring functional combinations. Furthermore, vulnerability to gastric acid requires stabilisation or formulation for rapid enteric release.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Enzymes should be stabilised throughout the gastrointestinal tract including the small intestine. Exopeptidases perform a critical function by systematically generating absorbable fractions, warranting future investigation as therapeutic agents. 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