Larazotide

Larazotide acetate (Gly-Gly-Val-Leu-Val-Gln-Pro-Gly; CAS 258818-34-7; molecular weight 754.86 free peptide) is an eight-residue synthetic peptide developed at the University of Maryland by Alessio Fasano and colleagues as a competitive antagonist at the zonulin receptor. Zonulin (also designated pre-haptoglobin 2) is the human ortholog of the Vibrio cholerae zonula occludens toxin (ZOT) and is the only known endogenous regulator of intestinal epithelial tight junction permeability; activation of the zonulin pathway in response to gluten exposure or other triggers produces transient opening of intestinal tight junctions and translocation of luminal antigens into the lamina propria, contributing to celiac disease pathogenesis and a broader leaky-gut phenotype implicated in autoimmune and inflammatory conditions. Larazotide binds the zonulin receptor and blocks ZOT/zonulin-induced tight junction disassembly without directly affecting baseline tight junction integrity. The compound was advanced through Phase 1 and Phase 2 trials in celiac disease and entered Phase 3 (CeDLara) for the residual gluten-cross-contamination phenotype in patients on a gluten-free diet who continue to experience symptoms. The Phase 3 readout in 2022 did not meet the primary endpoint of celiac disease patient-reported outcome, and 9 Meters Biopharma announced discontinuation of the program. Despite the clinical setback in celiac disease, larazotide remains a pharmacologically distinct research tool for tight junction modulation in inflammatory bowel disease, multiple sclerosis, and other indications where intestinal barrier dysfunction is implicated. Oral bioavailability is essentially zero (the peptide acts in the gut lumen and is not absorbed); the route of administration is per oral as a sustained-release formulation. Adverse events in clinical trials were mild and dominated by gastrointestinal effects.