Larazotide

Mechanism (as reported)

A study reported larazotide acetate as a tight junction regulator associated with redistribution/rearrangement of tight junction proteins and actin filaments to restore barrier function, and also linked it to inhibition of myosin light chain kinase (MLCK), reducing tension on actin filaments and facilitating tight junction closure. (PMIDs: 33881350) Another research report described larazotide acetate as a zonulin antagonist that specifically increases intestinal barrier integrity and can reduce arthritis onset in a preventive approach context. (PMIDs: 32332732) A keratinocyte study reported larazotide mitigating histamine-stimulated epithelial barrier disruption by increasing transepithelial electrical resistance and decreasing permeability, framed in that study as involving protease-activated receptor 2 antagonism. (PMIDs: 40579122) A modeling/synthesis/bioactivity study described earlier evidence that AT-1001 (larazotide acetate) binds the catalytic domain of SARS-CoV-2 3CLpro (Mpro). (PMIDs: 34502335)

Key findings (each cites a source)

• Larazotide acetate is described as a single-chain peptide of eight amino acids that acts as a tight junction regulator and is being studied in phase III clinical trials in celiac disease, described as orally administered as an adjunct to enhance intestinal barrier function. (PMIDs: 33881350) [PMID 33881350]
• Mechanistic work in the provided sources describes larazotide acetate as a zonulin antagonist associated with reducing zonulin-induced increases in barrier permeability and with redistribution/rearrangement of tight junction proteins and actin filaments to restore intestinal barrier function. (PMIDs: 33881350) [PMID 33881350]
• The provided sources also link larazotide acetate to inhibition of myosin light chain kinase (MLCK), described as reducing tension on actin filaments to facilitate tight junction closure. (PMIDs: 33881350, 40915363) [PMID 33881350, 40915363]
• Research reported that zonulin family peptide levels are high in autoimmune mice and humans and can predict transition from autoimmunity to inflammatory arthritis, with increased serum zonulin accompanied by leaky intestinal barrier, dysbiosis, and inflammation; in that study, restoration of intestinal barrier integrity using larazotide acetate reduced arthritis onset. (PMIDs: 32332732) [PMID 32332732]
• Animal studies in the provided sources are described as having been conducted for larazotide acetate beyond celiac disease, including collagen-induced arthritis in mice and intestinal ischemic injury in pigs. (PMIDs: 33881350) [PMID 33881350]
• A keratinocyte study reported larazotide’s protective effect against histamine-stimulated epithelial barrier disruption by increasing electrical resistance and decreasing epithelial permeability in keratinocyte monolayers, and framed larazotide as a protease-activated receptor 2 antagonist in that context. (PMIDs: 40579122) [PMID 40579122]
• A review described increased intestinal permeability as central to celiac disease pathophysiology and summarized therapies targeting barrier integrity, including larazotide acetate. (PMIDs: 40330848) [PMID 40330848]
• A celiac-focused piece described larazotide acetate (AT-1001) as a permeability regulator primarily targeting celiac disease, stating that in vitro studies indicate it can inhibit actin rearrangement caused by gliadin and that clinical studies have been conducted using it as therapy for celiac disease. (PMIDs: 26770266) [PMID 26770266]
• A modeling/synthesis/bioactivity study described prior evidence that the zonulin octapeptide inhibitor AT-1001 (larazotide acetate) binds the SARS-CoV-2 3CLpro (Mpro) catalytic domain, and reported cell-based assay investigation of antiviral activity of AT-1001 and derivatives. (PMIDs: 34502335) [PMID 34502335]
• A hydrogel-based research report described an injectable hyaluronic-acid hydrogel with sustained release of larazotide acetate as being developed to restore barrier integrity and modulate gut microbiota, reporting sustained release, inhibition of zonulin-mediated tight junction disruption via MLCK/p-MLC signaling in LPS-injured Caco-2 cells, and repair/upregulation of tight-junction and mucus-related markers and microbiota rebalancing in a DSS-induced colitis mouse model. (PMIDs: 40915363) [PMID 40915363]
• A review reported that a systematic search identified numerous publications on larazotide across several disease areas (including celiac disease and inflammatory diseases) and organized them by mechanism and disease, describing that a substantial role of the zonulin pathway in many chronic and acute inflammatory diseases has been demonstrated in both in vivo and in vitro contexts, and that new possible molecular targets for larazotide were discussed in the review. (PMIDs: 33397225) [PMID 33397225]