Larazotide
Larazotide is a synthetic eight-amino-acid peptide studied as an oral regulator of intestinal tight junctions. It reached phase 3 testing in celiac disease but is not approved for any use.
Overview
Larazotide, studied as larazotide acetate and earlier under the code AT-1001, is a short synthetic peptide designed to act locally in the gut lumen. Its development grew out of research on zonula occludens toxin from Vibrio cholerae and on zonulin, an endogenous protein proposed to regulate the tight junctions that seal the spaces between intestinal epithelial cells. Larazotide was intended to reduce excessive paracellular permeability, sometimes described as a leaky gut barrier, rather than to modulate the immune system directly.
The main clinical target was celiac disease, in which gluten fragments cross the intestinal barrier and trigger an immune response. Larazotide was evaluated as an adjunct to a gluten-free diet in people with persistent symptoms, progressing through phase 2 trials to a phase 3 program. Its development history has been uneven, and readers should check current sources for the program's status. Other research has explored barrier function in additional models, mostly preclinical.
Structure
Larazotide is a linear octapeptide with the sequence Gly-Gly-Val-Leu-Val-Gln-Pro-Gly (GGVLVQPG). It has free termini in the commonly described form and contains no cysteine, methionine or tryptophan. The clinical material was the acetate salt, and oral formulations were designed to release the peptide in the small intestine. Because it is short and largely hydrophobic apart from the glutamine residue, it is relatively simple to synthesize by solid-phase methods.
Mechanism
Larazotide is described as a tight junction regulator. In cell-culture and animal studies it has been reported to reduce the opening of tight junctions induced by gluten fragments and other stimuli, with effects on the distribution of tight junction proteins such as ZO-1 and on actin rearrangement in epithelial cells. It has been proposed to act by antagonizing zonulin-related signaling at the epithelial surface.
A specific receptor and complete signaling pathway have not been firmly established. Because the peptide is intended to act within the gut lumen with little systemic absorption, its effects are thought to be local to the intestinal epithelium.
Research
Celiac disease trials
Larazotide was studied in randomized, placebo-controlled trials in adults with celiac disease, both in gluten-challenge designs and in people with persistent symptoms despite a gluten-free diet. One phase 2b trial reported that a lower dose arm improved symptom scores compared with placebo, while higher doses did not show the same effect, an unusual dose-response pattern. These results supported progression to a phase 3 program, which was later reported to have been halted after an interim analysis.
Intestinal permeability measures
Several studies used urinary lactulose-to-mannitol ratios and similar tests to estimate intestinal permeability. Results across trials were inconsistent, and permeability changes did not always track with symptom outcomes. This illustrates a broader challenge in barrier research: permeability tests are indirect, variable, and only partly linked to clinical endpoints in people. Larazotide trials therefore reported permeability as an exploratory rather than decisive outcome.
Preclinical and in-vitro work
In cultured intestinal epithelial cell monolayers, larazotide has been reported to limit increases in permeability induced by gliadin fragments and inflammatory stimuli. Animal studies have examined its effect on barrier function in models of intestinal injury and inflammation. These findings support the proposed mechanism but are laboratory observations whose translation to human disease remains uncertain. Researchers also use larazotide as a pharmacological tool to probe how tight junctions respond to luminal stimuli in epithelial models.
Evidence quality
Larazotide is one of the few tight-junction-targeting peptides to reach late-stage clinical testing. Its phase 2 results were mixed and its phase 3 program did not lead to approval. The compound remains a useful reference for research on intestinal barrier regulation, but it should be regarded as investigational, with no established clinical benefit. Its trial history also illustrates how difficult it is to define meaningful endpoints for symptom-driven gastrointestinal conditions.
Regulatory status
Larazotide is not approved by the FDA or, as far as is publicly known, any other major regulator. It reached phase 3 testing in celiac disease, but that program was reported to have been halted; check current sources for its development status. It is not a recognized substance for US pharmacy compounding. For sport, check the current WADA Prohibited List.
Status changes often. See the regulatory tracker for dated updates.
Quality and identity testing
A certificate of analysis should confirm identity by mass spectrometry against the expected mass shown on this page and report HPLC purity with the chromatogram. Because the sequence is short and contains repeated Val and Gly residues, deletion impurities (missing Gly or Val) can be close in retention time to the main peak, so a well-resolved method and MS confirmation of impurity peaks are useful. The single glutamine can deamidate (+1 Da). The counter-ion, usually acetate, and net peptide content should be reported.
Open Larazotide in the sequence analyzer to see the expected [M+H]+ and multiply charged ions for an MS identity check.
For a walkthrough of each section of a certificate, see how to read a COA.
Storage and stability
Store lyophilized larazotide sealed at -20 °C or colder, protected from moisture and light, and allow vials to reach room temperature before opening. The peptide lacks oxidation-prone residues, so the main concerns are moisture uptake and slow deamidation of glutamine in solution. Prepare solutions in sterile water or buffer for lab use, keep them refrigerated for short-term work, aliquot for longer storage, and avoid repeated freeze-thaw cycles.
Download the Larazotide data sheet (PDF): sequence, masses, expected MS ions and handling on one printable page.
Latest research
The newest PubMed-indexed papers that mention Larazotide in their title or abstract, retrieved through Europe PMC and refreshed automatically. Inclusion is not an endorsement of a paper's findings.
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Frequently asked questions
Is larazotide FDA approved?
No. Larazotide is not approved by the FDA for any use. It was the subject of phase 2 trials and a phase 3 program in celiac disease, but the phase 3 program was reported to have been halted and no marketing approval followed. Its current development status should be checked in up-to-date sources.
What is the link between larazotide and zonulin?
Zonulin is a protein proposed to loosen intestinal tight junctions, and it was identified through research on a cholera toxin called zonula occludens toxin. Larazotide was developed as a peptide that counteracts this kind of tight junction opening. It is often described as a zonulin antagonist, although its exact molecular target has not been firmly established.
Is larazotide absorbed into the bloodstream?
Larazotide was designed to act locally in the small intestine, and oral formulations were made to release it in the gut lumen. Little systemic absorption is expected for a short peptide given this way, which is consistent with its intended local action on the intestinal epithelium. Detailed pharmacokinetic data in the public literature are limited.
Related compounds
- KPV
KPV is the tripeptide lysine-proline-valine, the C-terminal sequence of alpha-melanocyte-stimulating hormone. It is studied for anti-inflammatory effects in cell and rodent models, particularly of intestinal inflammation, and is not approved for any use.
- BPC-157
BPC-157 is a synthetic 15-amino-acid peptide whose sequence was derived from a protein fraction of gastric juice. It is studied mainly in rodent models of gastrointestinal, tendon and soft-tissue injury and is not approved for any use.
- VIP (vasoactive intestinal peptide)
Vasoactive intestinal peptide (VIP) is a 28-amino-acid neuropeptide of the secretin-glucagon family that acts on VPAC1 and VPAC2 receptors. It regulates smooth muscle, secretion and immune function, and synthetic VIP (aviptadil) has been studied clinically.
- LL-37
LL-37 is the 37-amino-acid antimicrobial peptide released from human cathelicidin hCAP18. It is studied for direct antimicrobial activity and immune-modulating effects in cell, animal and early human studies, and is not approved for any use.
References
- Leffler DA, Kelly CP, Green PH, et al. Larazotide acetate for persistent symptoms of celiac disease despite a gluten-free diet: a randomized controlled trial. Gastroenterology. 2015. Find on PubMed
- PubMed: all indexed literature on Larazotide
- ClinicalTrials.gov: registered studies mentioning Larazotide
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