GLUCHIRAL · Molecular chirality tools for the study of Gluten Immunogenic Peptides and Celiac Disease: Novel therapeutic and diagnostic approaches.

Celiac disease (CD) is a systemic autoimmune disorder triggered by gluten consumption in genetically predisposed individuals, affecting a substantial portion of the European population (1.4%). A significant number of CD cases remain undiagnosed (75%), leading to untreated disease and its associated symptoms. These range from immediate gastrointestinal and extra-intestinal distress to long-term complications such as osteoporosis, infertility, and cancer, among others, placing substantial strain on society and healthcare systems. As the primary treatment for CD remains a strict gluten-free diet, there is a pressing need for innovative approaches to alleviate the burden of inadvertent gluten exposure. This proposal aims to investigate the molecular mechanisms governing the transport of gluten immunogenic peptides (GIP) across the small intestine and to develop a chiral-based strategy for the design of enantiomeric peptides that can inhibit GIP toxicity and immunogenicity. Our objectives are: 1) To develop a focused library of enantiomeric peptide inhibitors of GIP that could be used as novel therapeutic agents for CD. 2) To elucidate the molecular mechanisms of GIP transport and immunogenicity across the small intestine using GIP enantiomers as probes. 3) To establish a liquid chromatography–mass spectrometry (LC-MS) assay for GIP quantitation in biological samples as a novel diagnostic tool for assessing gut permeability in CD patients. The successful accomplishment of these objectives will provide valuable insights into GIP activity and transport within intestinal epithelium and immune cells. Moreover, it offers the potential to identify novel peptide-based therapeutics against GIP, with the possibility of further commercialization. Lastly, the success of this proposal carries the critical importance of raising awareness about CD and pathologies associated with gluten consumption, addressing the alarming rate of undiagnosed cases within the European population.