Larazotide

Larazotide (AT-1001) is a synthetic octapeptide derived from the Vibrio cholerae zonula occludens toxin (Zot) that functions as a tight junction regulator. It was developed by Fasano and colleagues at the University of Maryland Center for Celiac Research as an oral research approach for celiac disease models and other conditions involving increased intestinal permeability. Larazotide acts locally in the gut lumen to prevent the disassembly of tight junction proteins, thereby reducing paracellular permeability — the passage of molecules and immune triggers between intestinal epithelial cells.

The mechanism of larazotide involves antagonism of the zonulin pathway. Zonulin is an endogenous human protein (identified as pre-haptoglobin-2) that reversibly modulates intestinal tight junctions by activating epidermal growth factor receptor (EGFR) and protease-activated receptor 2 (PAR2) signaling. In celiac disease, gluten-derived peptides trigger zonulin release, leading to increased intestinal permeability that allows immunogenic gluten fragments to access the lamina propria and activate immune responses. Larazotide blocks this process at the tight junction level.

Multiple Phase 2 research studies have evaluated larazotide acetate in research subjects with celiac disease on a gluten-free diet, with results showing reductions in intestinal permeability and improvements in gastrointestinal endpoints. The peptide has advanced to Phase 3 research evaluation. Because larazotide acts locally in the intestinal lumen with minimal systemic absorption, it has demonstrated a favorable profile in research studies. Research interest extends to other preclinical models associated with barrier-dysfunction markers, including inflammatory-bowel and irritable-bowel research models.