Mechanism of action of ZOT-derived peptide AT-1002, a tight junction regulator and absorption enhancer

Shobha Gopalakrishnan, Niranjan Pandey, Amir P. Tamiz, John Vere, Rosa Carrasco, Robert Somerville, Amit Tripathi, Mark Ginski, Blake M. Paterson, Sefik S. Alkan

Research output: Contribution to journalArticle

Abstract

Tight junctions (TJs) are intercellular structures that control paracellular permeability and epithelial polarity. It is now accepted that TJs are highly dynamic structures that are regulated in response to exogenous and endogenous stimuli. Here, we provide details on the mechanism of action of AT-1002, the active domain of Vibrio cholerae's second toxin, zonula occludens toxin (ZOT). AT-1002, a hexamer peptide, caused the redistribution of ZO-1 away from cell junctions as seen by fluorescence microscopy. AT-1002 also activated src and mitogen activated protein (MAP) kinase pathways, increased ZO-1 tyrosine phosphorylation, and rearrangement of actin filaments. Functionally, AT-1002 caused a reversible reduction in transepithelial electrical resistance (TEER) and an increase in lucifer yellow permeability in Caco-2 cell monolayers. In vivo, co-administration of salmon calcitonin with 1 mg of AT-1002 resulted in a 5.2-fold increase in AUC over the control group. Our findings provide a mechanistic explanation for AT-1002-induced tight junction disassembly, and demonstrate that AT-1002 can be used for delivery of other agents in vivo.

Original languageEnglish (US)
Pages (from-to)121-130
Number of pages10
JournalInternational Journal of Pharmaceutics
Volume365
Issue number1-2
DOIs
StatePublished - Jan 5 2009

Keywords

  • AT-1002
  • Mechanism of action
  • Permeability
  • Tight junctions

ASJC Scopus subject areas

  • Pharmaceutical Science

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    Gopalakrishnan, S., Pandey, N., Tamiz, A. P., Vere, J., Carrasco, R., Somerville, R., Tripathi, A., Ginski, M., Paterson, B. M., & Alkan, S. S. (2009). Mechanism of action of ZOT-derived peptide AT-1002, a tight junction regulator and absorption enhancer. International Journal of Pharmaceutics, 365(1-2), 121-130. https://doi.org/10.1016/j.ijpharm.2008.08.047