Larazotide

Research Of Larazotide

1.Target Identification and Drug Design

Zonulin, the protein that regulates small intestinal (SI) paracellular permeability in a reversible and inducible fashion was discovered.

Even if the mode of action of Larazotide is analogous to that AT-1001–that is to say, a blockade of zonulin binding to its receptor and through this prevention of increased intestinal permeability by attenuation of zonulin from tight junctions-, it was tested as the first TJ modulator in humans.

However, owing to its distinct amino acid sequence and acetate salt formulation (Larazotide acetate, CAS No 881851-50-9), Larazotide [Ac-KPFSLSQ(Cys)] demonstrates superior stability and local bioavailability in the gut.

2.Modulation of Intestinal Barrier Function

Larazotide holds profound scientific value as a new and dynamic approach to the specific modulation of intestinal barrier function.

Its action is mainly exerted through being a structural analogue of zonulin, competing with zonulin for binding to the receptors on the luminal surface of enterocytes.

This leads to inhibition of intracellular activation of myosin light-chain kinase (MLCK), cytoskeletal reorganization and disassembly of tight junction proteins including ZO-1.

By this molecular mechanism Larazotide secures barrier integrity of tight junctions and inhibits unwanted translocation of macromolecules e.g., gliadin.

3.Management of Celiac Disease

Celiac disease (CD) is an autoimmune enteropathy, initiated by the exposure to gluten in genetically predisposed individuals, and it affects about 1% of worldwide population.

At present, adherence to gluten-free diet is the only proven therapy.

However, long-term adherence to the diet is difficult; strict avoidance of cross-contact may be hard to achieve and symptoms persist in many patients.

At its core, the MOA of Larazotide in celiac disease is selective inhibition of zonulin-induced TJ opening.

In celiac disease, in response to deamidated gliadin peptides, enterocyte CXCR3 is engaged leading to release of zonulin.

The free zonulin then interacts with its receptor on the epithelial layer, triggering intracellular signaling pathways that lead to myosin light-chain phosphorylation.

This results in the relocalization of tight junction proteins (such as ZO-1, occludin and claudins) and cytoskeleton rearrangement with a consequent enhancement of intestinal permeability.

Larazotide is a competitive octapeptide antagonist, competitively and reversibly binds to zonulin receptors on the luminal surface of epithelial cells, thereby blocking this cascade signaling process, and maintains barrier homeostasis.

A landmark Phase IIb clinical trial included 342 patients with continued symptoms in the setting of a GFD.

A dose of 0.5 mg three times daily was shown to be effective and superior to placebo in terms of reduction of gastrointestinal symptoms with an acceptable safety and tolerability profile prior to further study.

4.Antiviral Properties

Apart from its application in intestinal inflammation, Larazotide has marked in vitro antiviral efficacy against VZV.

This discovery extends its therapeutic potential and indicates diverse mechanisms of action may be operative.

The in vitro evidence suggests that Larazotide inhibits the replication of VZV OKA and 07-1 strains with EC₅₀ of 44.14 μM and 59.06 μM, respectively.

This level of activity is moderate for an antiviral agent.

However, as the activity of Larazotide is localized with a relatively large therapeutic window, this adds to substantial value in clinical development.

Notably, the cytotoxicity of this agent in host cells (Vero cells) demonstrated a CC₅₀ value of 82.5 μM, providing a TI ratio of ~1.4–1.9.

This suggests a modest but presumably acceptable safety factor at antiviral concentrations which are effective.