Open main menu

Larazotide

  (Redirected from Larazotide acetate)

Larazotide (INN; also known as AT-1001; formulated as the salt with acetic acid, larazotide acetate) is a synthetic eight amino acid peptide that functions as a tight junction regulator and reverses leaky junctions to their normally closed state. It is being studied in people with celiac disease.

Larazotide
Larazotide.svg
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
ChemSpider
KEGG
Chemical and physical data
FormulaC32H55N9O10
Molar mass725.85 g·mol−1
3D model (JSmol)

Contents

StructureEdit

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 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.[1][2]

Mechanism of actionEdit

Larazotide is an inhibitor of paracellular permeability. In celiac disease, one pathway that allows fragments of gliadin protein to get past the intestinal epithelium and subsequently trigger an immune response begins with binding of indigestible gliadin fragments to the chemokine CXC motif receptor 3 (CXCR3) 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.[3][4]

OriginEdit

Larazotide acetate is a synthetic peptide based on a Vibrio cholerae enterotoxin called zonula occludens toxin that increases intestinal permeability. 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. The responsible region was located near the carboxyl terminus 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, an endogenous protein involved in tight junction modulation. This sequence was later designated larazotide acetate.[5]

ReferencesEdit

  1. ^ Pubchem. "Larazotide acetate | C34H59N9O12 - PubChem". pubchem.ncbi.nlm.nih.gov. Retrieved 2016-04-16.
  2. ^ "ChemIDplus - a TOXNET database". Retrieved 16 April 2016.
  3. ^ Fasano, Alessio (2011-01-01). "Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer". Physiological Reviews. 91 (1): 151–175. doi:10.1152/physrev.00003.2008. ISSN 0031-9333. PMID 21248165.
  4. ^ Khaleghi, Shahryar; Ju, Josephine M.; Lamba, Abhinav; Murray, Joseph A. (2016-01-01). "The potential utility of tight junction regulation in celiac disease: focus on larazotide acetate". Therapeutic Advances in Gastroenterology. 9 (1): 37–49. doi:10.1177/1756283X15616576. ISSN 1756-283X. PMC 4699279. PMID 26770266.
  5. ^ Di Pierro, M.; Lu, R.; Uzzau, S.; Wang, W.; Margaretten, K.; Pazzani, C.; Maimone, F.; Fasano, A. (2001-06-01). "Zonula occludens toxin structure-function analysis. Identification of the fragment biologically active on tight junctions and of the zonulin receptor binding domain". The Journal of Biological Chemistry. 276 (22): 19160–19165. doi:10.1074/jbc.M009674200. ISSN 0021-9258. PMID 11278543.

External linksEdit