Selective Inhibition Of Different Isoforms Of Connexin Hemichannels By New Aminoglycosides

Connexins hemichannels (HCs) from adjacent cells form gap-junctional channels that mediate cell-to-cell communication. Abnormal opening of “free” undocked HCs can produce cell damage and participate in the mechanism of disorders such as cardiac infarct, stroke, deafness, skin diseases, and cataracts. Connexin 43 (Cx43) HCs play a role in cardiac infract and stroke, whereas abnormally active connexin 26 (Cx26) HCs have been associated with deafness. Therefore, selective inhibitors of connexin HCs have great pharmacological potential. Antibiotic aminoglycosides (AGs) have been recently identified as connexin HC inhibitors. Here, we synthesized and tested several amphiphilic AGs derived from kanamycin that do not have antibiotic effect, but still inhibit connexin HCs. Using a newly developed cell-based bacterial growth complementation assay we found several leads with superior inhibitory potency on Cx43 vs. Cx26 HCs when compared to the parent compound, kanamycin A. Unlike traditional AGs, these amphiphilic AGs are not bactericidal and are not toxic to mammalian cells, making them better than traditional AGs as HC inhibitors for clinical use and other applications. This work was supported in part by NSF Award CHE-1429195 for a 500 MHz Bruker NMR, American Heart Association Texas Affiliate Inc. grant 14GRNT18750014, and a TTUHSC Preliminary Data Grant.