Larazotide (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

; also known as AT-1001; formulated as the

salt Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quantitie ...

with

acetic acid Acetic acid , systematically named ethanoic acid , is an acidic, colourless liquid and organic compound with the chemical formula (also written as , , or ). Vinegar is at least 4% acetic acid by volume, making acetic acid the main component ...

, larazotide acetate) is a synthetic eight

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...

that functions as a

tight junction Tight junctions, also known as occluding junctions or ''zonulae occludentes'' (singular, ''zonula occludens''), are multiprotein junctional complexes whose canonical function is to prevent leakage of solutes and water and seals between the epith ...

regulator and reverses leaky junctions to their normally closed state. It is being studied in people with

celiac disease Coeliac disease (British English) or celiac disease (American English) is a long-term autoimmune disorder, primarily affecting the small intestine, where individuals develop intolerance to gluten, present in foods such as wheat, rye and barl ...

Structure

Larazotide is an octapeptide whose structure is derived from a protein (zonula occludens toxin) secreted by ''Vibrio cholerae''. It has the amino acid sequence GGVLVQPG,

IUPAC The International Union of Pure and Applied Chemistry (IUPAC ) is an international federation of National Adhering Organizations working for the advancement of the chemical sciences, especially by developing nomenclature and terminology. It is ...

condensed descriptor of H-Gly-Gly-Val-Leu-Val-Gln-Pro-Gly-OH, and the systematic name glycylglycyl-L-valyl-L-leucyl-L-valyl-L-glutaminyl-L-prolyl-glycine.

Mechanism of action

Larazotide is an inhibitor of paracellular permeability. In

, one pathway that allows fragments of

gliadin Gliadin (a type of prolamin) is a class of proteins present in wheat and several other cereals within the grass genus ''Triticum''. Gliadins, which are a component of gluten, are essential for giving bread the ability to rise properly during baki ...

protein to get past the intestinal epithelium and subsequently trigger an

immune response An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which could ...

begins with binding of indigestible gliadin fragments to the

chemokine Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additio ...

CXC motif receptor 3 (

CXCR3 Chemokine receptor CXCR3 is a Gαi protein-coupled receptor in the CXC chemokine receptor family. Other names for CXCR3 are G protein-coupled receptor 9 (GPR9) and CD183. There are three isoforms of CXCR3 in humans: CXCR3-A, CXCR3-B and chemoki ...

) on the luminal side of the intestinal epithelium (see this page). This leads to the induction of myeloid differentiation factor 88 ( MYD88) and the release of zonulin into the lumen. Zonulin then binds to epidermal growth factor receptor (EGFR) and protease-activated receptor 2 (PAR2) in the intestinal epithelium. This complex then initiates a signalling pathway that eventually results in tight junction disassembly and increased intestinal permeability. Larazotide acetate intervenes in the middle of this pathway by blocking zonulin receptors, thereby preventing tight junction disassembly and associated increase in intestinal permeability.

Origin

Larazotide acetate is a

synthetic peptide In organic chemistry, peptide synthesis is the production of peptides, compounds where multiple amino acids are linked via amide bonds, also known as peptide bonds. Peptides are chemically synthesized by the condensation reaction of the carboxyl ...

based on a ''

Vibrio cholerae ''Vibrio cholerae'' is a species of Gram-negative, facultative anaerobe and comma-shaped bacteria. The bacteria naturally live in brackish or saltwater where they attach themselves easily to the chitin-containing shells of crabs, shrimps, and oth ...

enterotoxin An enterotoxin is a protein exotoxin released by a microorganism that targets the intestines. Enterotoxins are chromosomally encoded or plasmid encoded exotoxins that are produced and secreted from several bacterial organisms. They are heat labi ...

called zonula occludens toxin that decreases

intestinal permeability Intestinal permeability is a term describing the control of material passing from inside the gastrointestinal tract through the cells lining the gut wall, into the rest of the body. The intestine normally exhibits some permeability, which allows ...

. An investigation was carried out to discover which specific part of this toxin was responsible for this activity. Several mutants were constructed and tested for their biological activity and their ability to bind to intestinal epithelial cells in

culture Culture () is an umbrella term which encompasses the social behavior, institutions, and norms found in human societies, as well as the knowledge, beliefs, arts, laws, customs, capabilities, and habits of the individuals in these groups.Tyl ...

. The responsible region was located near the

carboxyl terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

of the toxin protein. This region coincided with a peptide product generated by ''Vibrio cholerae''. The eight amino acid sequence in this region was shared with

zonulin Zonulin (haptoglobin 2 precursor) is a protein that increases the permeability of tight junctions between cells of the wall of the digestive tract. It was discovered in 2000 by Alessio Fasano and his team at the University of Maryland School of ...

, an endogenous protein involved in tight junction modulation. This sequence was later designated larazotide acetate.

Research

It's been used in experiments related to

arthritis Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In som ...

References

{{Reflist Experimental drugs Drugs acting on the gastrointestinal system and metabolism Peptides