Xentry-Gap19™

Xentry-Gap19 is a hemichannel blocking peptidomimetic (Gap19) linked to the unqiue cell penetrating sequence, Xentry. Xentry-Gap19 is Connexin43 specific and closes pathological Connexin43 hemichannels, so inhibiting release of ATP and activation of the inflammasome pathway. Unlike orally dosed Xiflam, Gentry-Gap19 is a peptide with a short half-life for rapid intervention where the pharmacokinetics ensures high bioavailability in a short period of time. This includes acute events such as stroke, myocardial infarction, retinal artery and vein occlusion, where the need to rapidly block hemichannel opening upon reperfusion is critical to the survival of the affected tissue.

Gap19 is a Cx43 hemichannel blocker derived from the second cytoplasmic loop of Cx43. It blocks the interaction that occurs between the Cx43 protein’s intracellular loop and C-terminal tail that causes hemichannel opening (and conversely gap junction closure). Gap19 needs to enter the cell in order to bind to the corresponding sequence of the cytoplasmic tail of Cx43. The cell penetrating peptide Xentry is derived from the X-protein of the hepatitis B virus and has been shown to efficiently transport a range of molecules into cells via endocytic mechanisms by binding to cell surface – expressed Syndecan-4. Syndecan-4 is upregulated under pathological conditions, especially hypoxia, enabling targeting of Xentry-Gap19 to sites of injury and inflammation. Because Syndecan-4 is not expressed on circulating monocytes and erythrocytes, sequestration by the circulation, if delivered systemically, is prevented,