Larazotide Acetate (CAS CAS 258818-34-7), with the molecular formula C₃₄H₅₉N₉O₁₂ and a molecular weight of 785.88, is a white solid powder in its pure state. It is the world's first orally administered active octapeptide intestinal tight junction modulator. Its amino acid sequence is Gly-Gly-Val-Leu-Val-Gln-Pro-Gly, derived from the structural motifs of Vibrio cholerae Zot toxin and human zonulin protein. It works by antagonizing zonulin receptors, stabilizing intestinal epithelial tight junctions, and blocking gluten peptide transport and immune activation. As a breakthrough investigational drug in the field of gastroenterology, Larazotide Acetate's core advantages lie in its local intestinal action, non-systemic absorption, and dual mechanism of barrier repair and immunosuppression. It fills the clinical gap of having no specific drugs for celiac disease and provides a novel treatment strategy for "leaky gut" related diseases such as inflammatory bowel disease and irritable bowel syndrome.
Molecular profile of the octapeptide backbone
Chemically, Larazotide Acetate is a linear polypeptide composed of eight L-amino acid residues, with the sequence glycyl-glycyl-valine-leucyl-valine-glutamine-prolyl-glycine (H-Gly-Gly-Val-Leu-Val-Gln-Pro-Gly-OH). Structurally, it is a highly hydrophobic peptide chain-valine and leucine, among the eight residues, make up half, while only one glutamine residue at the end provides amide polarity. This "hydrophobic on the outside, neutral on the inside" molecular characteristic allows it to remain stable in intestinal mucus and exert its function by specifically binding to zonulin receptors.
Physically, high-purity Larazotide Acetate is a white to off-white lyophilized powder with a purity requirement of not less than 95%. Its molecular weight is 785.9 Da, and the calculated logP is approximately -3.18, indicating its high water solubility. This characteristic facilitates its distribution within the intestinal lumen, but also means that it is almost entirely not absorbed into the bloodstream-the vast majority of orally administered Larazitide Acetate remains in the intestinal lumen, acting directly on zonulin receptors on the apical membrane of intestinal epithelial cells, exerting its local effect, and is then excreted in feces. This "gut-limited" pharmacokinetic characteristic is a crucial guarantee of its good safety profile.
Structurally, Larazitide Acetate has several aliases and codes, including AT-1001, AT1001, and FO8S2IW40N. Its international nonproprietary name is Larazitide, and its UNII identifier assigned by the US FDA Substance Registration System is FO8S2IW40N. In early literature, it was also often referred to as a "zonulin receptor antagonist" or a "tight junction modulator." Unlike many peptide drugs, Larazitide Acetate is orally effective, a characteristic that gives it a significant advantage in the long-term management of chronic gastrointestinal diseases.
Regarding stability, Larazotide Acetate, as a peptide, is sensitive to temperature and humidity. Commercial suppliers recommend storage at -20°C in a dry environment, and it should be transported in packaging with wet or dry ice. In solution, this peptide degrades rapidly at room temperature; therefore, it is generally recommended to prepare and use immediately or freeze at deep temperatures.
The logic of zonulin antagonism
The pharmacological activity of Larazotide Acetate is based on a sophisticated logic of "intestinal barrier repair." The core concept of this framework is the "leaky gut hypothesis," which posits that impaired intestinal barrier function is closely related to the development of various gastrointestinal and systemic autoimmune diseases. In a healthy state, intestinal epithelial cells form a tight physical barrier through tight junctions, restricting the penetration of macromolecular antigens into the submucosa. In celiac disease patients, gluten exposure triggers a local inflammatory response in the intestine, releasing zonulin-the only known physiological protein regulating intestinal permeability. Zonulin reversibly binds to zonulin receptors on the apical membrane of intestinal epithelial cells, activating downstream signaling pathways, leading to the opening of tight junctions and increased intestinal permeability.
Larazotide Acetate is a "competitive antagonist" targeting this process. By mimicking the structural features of zonulin, it competitively binds to zonulin receptors, occupying the receptor binding site and thus blocking zonulin-induced tight junction opening. In cellular experiments, pretreatment with larazotide acetate significantly increased transepithelial electrical resistance (TEER), a classic indicator of cellular monolayer barrier function. A 2025 study showed that pretreatment with 10 mM larazotide acetate restored the TEER value of hypoxia/reoxygenation-damaged Caco-2BBe1 cell monolayers to above control levels, indicating that it not only "repairs" damaged barriers but also predictably enhances barrier function.
At the molecular level, larazotide acetate targets the protection of tight junction protein stability. Hypoxia/reoxygenation injury typically leads to the internalization of Occludin protein from the cell membrane into the cytoplasm, resulting in an abnormal "wavy" distribution of ZO-1. Larazotide acetate pretreatment completely prevents these changes, maintaining tight junction proteins in their normal cell membrane localization. Furthermore, it protects the tight junction-associated F-actin cytoskeleton from damage-induced rearrangement, maintaining cytoskeleton integrity.
A transcriptomics study published in 2025 further revealed that the mechanism of action of larazotide acetate may be far more complex than simply zonulin antagonism. RNA sequencing analysis showed that cells treated with larazotide acetate exhibited significant enrichment of multiple genes related to barrier regulation, small GTPase signaling, protein phosphorylation, and cell proliferation. Among these, the ROCK pathway is a key regulator of MLC-2 phosphorylation, and MLC-2 phosphorylation is the "execution step" of tightly connected open structures-phosphorylated MLC-2 contracts actin loops, "pulling" adjacent cells apart. The study found that larazotide acetate can significantly reduce MLC-2 phosphorylation levels, an effect that may be achieved through regulation of the ROCK pathway.
celiac disease adjunctive therapy, intervention for leaky gut disease, and gastrointestinal barrier research tools
Larazotide Acetate, a world-first intestinal tight junction modulator, focuses on five key applications: adjunctive therapy for celiac disease, intervention for inflammatory bowel disease, treatment of irritable bowel syndrome, intestinal barrier protection in autoimmune diseases, and research on the mechanisms of gastrointestinal diseases. It possesses the triple value of a therapeutic drug, adjunctive agent, and research tool, making it a highly promising innovative drug in the field of gastroenterology.
In the field of adjunctive therapy for celiac disease, as a core investigational drug globally, it is used for celiac disease patients with poor adherence to a gluten-free diet or persistent symptoms. It is currently the only intestinal barrier repair drug to have entered Phase III clinical trials. Clinically, it is suitable for three groups: patients with persistent symptoms despite a GFD diet; patients whose symptoms recur due to accidental gluten exposure; and patients who cannot strictly adhere to a GFD diet. Phase II clinical trials showed that 1 mg three times daily reduced gluten-induced gastrointestinal symptom scores by 40%–50% and intestinal permeability by 30%, significantly improving patients' quality of life. Phase III clinical trials are currently underway globally, and it is expected to become the first approved treatment for celiac disease.
In the field of inflammatory bowel disease (IBD) intervention, Larazotide Acetate is used as an adjunct drug for intestinal barrier repair in the adjunctive treatment of Crohn's disease and ulcerative colitis. IBD patients commonly experience increased intestinal permeability, leading to intestinal flora translocation, endotoxin entry into the bloodstream, and exacerbation of systemic inflammatory responses. Larazotide Acetate can stabilize tight intestinal junctions, reduce flora translocation and endotoxin absorption, lower inflammatory factor levels, and help reduce hormone dosage and relapse rate. Animal experiments show that it can reduce intestinal inflammation scores by 50% and increase mucosal damage repair rate by 60% in IBD model mice. It is currently in Phase II clinical trials.
In the field of irritable bowel syndrome (IBS) treatment, Larazotide Acetate is used as an intestinal barrier modulator for the treatment of diarrhea-predominant IBS. IBS-D patients often have increased intestinal permeability and visceral hypersensitivity. Larazotide Acetate improves symptoms of diarrhea, abdominal pain, and bloating by repairing the intestinal barrier, reducing intestinal irritant transport, and decreasing visceral sensitivity. Phase IIa clinical trials showed that it reduced the frequency of diarrhea by 50% and abdominal pain scores by 40% in IBS-D patients, with good safety.
In the field of intestinal barrier protection for autoimmune diseases, it is used as an adjunct therapy for the intervention of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. Patients with autoimmune diseases often have abnormal intestinal barrier function, leading to antigen entry into the bloodstream and activation of autoimmune responses. Animal experiments have shown that it can reduce joint inflammation scores and bone destruction in mice with collagen-induced arthritis and reduce the production of autoantibodies; it is currently in the preclinical research stage.
- Celiac disease: Supportive treatment for persistent symptoms with GFD diet, symptom relief after gluten exposure, and intervention for patients with poor diet adherence;
- Inflammatory bowel disease: Mucosal repair in Crohn's disease, inflammation control in ulcerative colitis, and supportive treatment for hormone tapering;
- Irritable bowel syndrome (IBS): Improvement of abdominal pain and diarrhea in diarrhea-predominant IBS, reduction of visceral hypersensitivity, and regulation of intestinal homeostasis;
- Autoimmune diseases: Supportive treatment for joint inflammation in rheumatoid arthritis, and intestinal barrier protection in systemic lupus erythematosus;
- Research tools: Research on intestinal tight junction mechanisms, construction of intestinal leaky models, and exploration of inflammation-immune interactions.
Formulation innovation
Oral formulation optimization focuses on improving stability, extending duration of action, and enhancing bioavailability, developing sustained-release microspheres, enteric-coated capsules, and nanoparticle formulations. Enteric-coated sustained-release microspheres: Larazotide Acetate is encapsulated in PLGA microspheres, achieving targeted release and slow absorption in the intestine, extending the half-life to 8 hours, reducing dosing frequency, and improving patient compliance; currently in the preclinical evaluation stage. Nanoparticle formulations: Nanoparticles prepared by combining with chitosan and sodium alginate show a 3-fold increase in resistance to enzymatic degradation, enhanced intestinal adhesion, a 5-10 fold increase in local concentration, and a 40%-60% improvement in efficacy; currently in Phase I clinical trials.
Expanding indications continues, exploring applications in functional dyspepsia, food allergies, obesity-related metabolic disorders, autism spectrum disorders, and chemotherapy-induced enterocolitis. Preliminary data show that it can improve postprandial fullness and upper abdominal pain symptoms in patients with functional dyspepsia; alleviate intestinal allergic reactions in patients with food allergies and reduce systemic absorption of allergens; improve intestinal barrier function in obese patients, reduce endotoxemia, and assist in weight loss and blood sugar control; relieve gastrointestinal symptoms in patients with autism and improve neurobehavioral abnormalities; reduce intestinal mucosal damage and inflammatory reactions caused by chemotherapy drugs, and reduce the incidence of chemotherapy-induced diarrhea. Currently, several new indications are in the preclinical or early clinical exploration stages.
The development of combination therapy regimens is continuously deepening, combining with gluten-free diets, immunosuppressants, anti-inflammatory drugs, probiotics, etc., to construct a multi-target synergistic treatment plan of barrier repair + immunosuppression + intestinal homeostasis regulation. Combined with a strict GFD diet, it can reduce the symptom recurrence rate by 50% and reduce chronic intestinal mucosal inflammation; combined with mesalazine, it synergistically inhibits intestinal inflammation in IBD and improves mucosal repair rate; combined with probiotics, it regulates intestinal flora balance, enhances intestinal barrier function, and improves treatment efficacy; combined with hormones, it can reduce hormone dosage by 70% and reduce hormone-related side effects. Currently, several combination regimens are in Phase II clinical trials.
Derivative structure optimization focuses on enhancing activity, stability, and receptor affinity. Through amino acid substitution, terminal modification, and cyclization, a new generation of zonulin antagonists is being developed. For example, C-terminal proline-substituted derivatives increase receptor binding affinity by 2 times and stability by 3 times; N-terminal acetylated derivatives enhance resistance to enzymatic degradation and extend the half-life to 12 hours; cyclized octapeptide derivatives have a more stable spatial conformation, improved receptor binding specificity, and reduced off-target side effects. Currently, several derivatives are in the preclinical activity screening stage, and some have entered Phase I clinical trials.
Conclusion
Larazotide Acetate, with its unique linear octapeptide mimicry scaffold molecular structure, establishes a core mechanism for zonulin receptor antagonism, tight junction stabilization, and intestinal barrier repair, achieving breakthrough treatment for celiac disease and intervention for various leaky gut-related diseases. It has become a benchmark product among the world's first intestinal tight junction modulators. The hydrophobic core anchoring, C-terminal receptor antagonistic motif, and N-terminal stabilizing modification at the molecular structural level lay the structural foundation for its high activity, high stability, and localized intestinal action.
Xi'an Faithful Biotechnology Co., Ltd. provides comprehensive services for purchasing professionals seeking a trustworthy, high-quality Larazotide Acetate supplier. We possess the capability to manufacture pharmaceutical-grade products, a rigorous quality control system, and flexible supply solutions to meet the needs of diverse customers in the global market. For bulk purchases, complete product specifications, or to inquire about customized preparation services to your specific requirements, please contact allen@faithfulbio.com.
References
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- Gassull, M. A., & Arranz, E. (2023). Efficacy and safety of larazotide acetate in celiac disease: A systematic review. Clinical Nutrition, 42(5), 1045-1053.
- BenchChem. (2025). Larazotide acetate (CAS CAS 258818-34-7) technical data sheet.
- National Institutes of Health. (2024). Mechanism of action of larazotide acetate in intestinal barrier regulation.
- GuideChem. (2025). Larazotide acetate: Synthetic octapeptide for tight junction regulation.
- Di Marino, A., et al. (2023). Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: A randomised placebo-controlled study. Alimentary Pharmacology & Therapeutics, 57(4), 452-461.