Larazotide

Larazotide is a synthetic peptide of eight amino acids, Gly-Gly-Val-Leu-Val-Gln-Pro-Gly, studied as a regulator of tight junctions, the seals between epithelial cells (Slifer et al., 2021a). Trials used its acetate salt, larazotide acetate, coded AT-1001 (Hoilat et al., 2022). It is described as structurally related to zonula occludens toxin (Zot), a Vibrio cholerae protein that opens tight junctions, and as an inhibitor of zonulin.

It reached phase 3 testing in celiac disease, and that trial was discontinued in June 2022 (Machado, 2023).

PubChem CID 9810532 lists the same formula, weight and CAS number for the free peptide and is the source of the sequence and the AT-1001 alias; CID 44146842 gives the acetate salt figures. INN-202 and FZI/0 are names from the literature (Tajik et al., 2020; Vanuytsel et al., 2021). Confirm from the certificate whether the capsules hold the free peptide or the acetate salt.

Published work on larazotide falls into five areas. Each summary below states the model used. Much of the cell and animal work comes from the developers or groups they funded.

Origin: a cholera toxin, zonulin and an octapeptide

Comparing the amino-terminal end of zonulin, a proposed human regulator of tight junctions, with the active fragment of Zot revealed a shared motif. A synthetic octapeptide based on it, GGVLVQPG, was named FZI/0, then AT1001 and later larazotide. Alone it did not change permeability, but pretreatment protected against purified Zot or zonulin (Vanuytsel et al., 2021).

Its developer, Alba Therapeutics, described its structure as derived from a Vibrio cholerae protein (Paterson et al., 2007). The zonulin link is debated. Critics argue that the proteins identified as zonulin, including prehaptoglobin-2, lack the octapeptide sequence; Alessio Fasano, whose group described zonulin, replied that zonulin is a family of related proteins (Veres-Székely et al., 2023). Models: tissue experiments summarized in reviews.

Tight junctions in epithelial cell models

In Caco-2 and IEC6 intestinal cells, larazotide acetate blocked the redistribution of ZO-1 and actin caused by gliadin fragments and by AT-1002, a six-residue Zot-derived peptide. In Caco-2 monolayers it prevented the AT-1002-induced fall in transepithelial electrical resistance (TEER), reduced passage of a gliadin 13-mer and blunted cytokine-driven permeability increases (Gopalakrishnan et al., 2012a).

In MDCK cells it promoted tight junction assembly in a calcium switch assay, and it lowered permeability in leaky Caco-2 monolayers (Gopalakrishnan et al., 2012b). In C2BBe1 and IPEC-J2 monolayers under anoxia and reoxygenation, pretreatment kept TEER higher and reduced myosin light chain 2 phosphorylation, which the authors tie to the ROCK pathway (Kim et al., 2025). Models: human, rat, dog and pig epithelial cell lines.

Animal and tissue models

In gliadin-sensitized HLA-HCD4/DQ8 transgenic mice, larazotide acetate limited intestinal macrophage accumulation and preserved tight junction structure (Gopalakrishnan et al., 2012a). IL10-deficient mice, which develop colitis spontaneously, had markedly lower small intestinal permeability on AT-1001 and less colonic TNF-alpha release at 17 weeks; the peptide acted only in the small intestine (Arrieta et al., 2009).

In mice with collagen-induced arthritis, ten days of larazotide shortly before onset prevented the permeability rise and reduced arthritis scores, synovitis and osteoclast numbers (Tajik et al., 2020). In ischemia-injured pig jejunum in Ussing chambers, 1 µM larazotide acetate raised electrical resistance above injured controls, while 0.1 µM and 10 µM did not (Slifer et al., 2021b). Models: mice and pig tissue ex vivo (animal data only).

Celiac disease trials

In a small inpatient trial in celiac disease, adverse events were no more frequent with AT-1001 than with placebo, and intestinal permeability, an exploratory measure, rose 70 percent after gluten with placebo but not with AT-1001 (Paterson et al., 2007).

In a 14-day trial in 86 participants, the primary endpoint, the lactulose/mannitol permeability ratio, was too variable to assess, while some lower amounts appeared to limit gluten-induced symptom worsening (Leffler et al., 2012). Over a six-week gluten challenge in 184 participants, the ratio again did not differ, the lowest of three amounts limited symptoms, and all three blunted the rise in anti-tissue transglutaminase IgA (Kelly et al., 2013).

In the phase 2b trial, 342 adults with persistent symptoms on a gluten-free diet received placebo or one of three amounts for 12 weeks. Only the lowest amount met the primary symptom endpoint, and adverse events were comparable with placebo (Leffler et al., 2015). A meta-analysis of four trials with 626 participants found no change in the permeability ratio and better symptom scores only under gluten challenge (Hoilat et al., 2022). Models: human trials and a meta-analysis.

Phase 3 outcome and current status

The phase 3 trial CeDLara (NCT03569007) planned to enroll 525 symptomatic adults on a gluten-free diet. An interim analysis at about half that enrollment showed no meaningful effect, and the study was discontinued in June 2022 (Machado, 2023). That review links the phase 2 pattern, where lower amounts did better, to possible peptide fragmentation or aggregation.

Separately, in a phase 2a placebo-controlled trial in 12 children with multisystem inflammatory syndrome after COVID-19, larazotide was added to standard care for three weeks; no larazotide-related adverse events were reported, and spike antigen and gastrointestinal symptoms cleared faster (Yonker et al., 2025). Models: human trials and a review.