Development of a Novel cAMP–Inhibitor that Restores Epithelial and/or Endothelial Barrier Integrity in Human Cells Infected by Pathogenic Bacteria
The current inhibitor provides an alternative strategy for the treatment of diseases caused by anthrax, cholera or pertussis toxins.
The inhibitor, ES109 is a potential therapeutic for the treatment of the diseases caused by anthrax, cholera or pertussis toxins and can restore, preserve, or both, epithelial and endothelial barrier integrity.
Researchers at UC San Diego have developed a strategy to block the pathogenic effects of Anthrax Edema Toxin (ET) and Cholera Toxin (CT) which represent key virulence factors for the respective pathogens, Bacillus anthracis and Vibrio cholerae. These toxins disrupt vascular endothelial (ET) and intestinal epithelial (CT) barrier integrity by blocking transport of adhesion proteins such as cadherins and signaling molecules to cell-cell junctions. As discussed above, ET and CT both act to dramatically elevate cAMP levels in the cell, but by distinct mechanisms. Two well-known cAMP binding proteins mediate the effects of cAMP in host cells: protein kinase A (PKA) and EPAC, a guanine nucleotide exchange factor for the small GTPase Rap1. Our invention uses a small molecule inhibitor (ESI09) of Rap1 to protect against the barrier disruptive effects of ET and CT, and to fortify endothelial and epithelial integrity in a wide variety of medical conditions in which barrier dysfunction is an important pathophysiologic feature.
State Of Development The soluble cell permeant EPAC/Rap1 inhibitor ESI09 has been shown to dramatically inhibit ET induced edema in vivo in a mice model. Additional studies were performed using both transgenic Drosophila and mammalian systems to dissect the role of ESI09 to bind the cAMP binding site on EPAC to prevent activation of EPAC. Intellectual Property Info A provisional patent has been submitted and the technology is available for licensing. Related Materials Tech ID/UC Case 29420/2017-070-0 Related Cases 2017-070-0
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