6th Global Summit on Toxicology and Applied Pharmacology
University of Arkansas for Medical Sciences, USA
Title: Identification of cell death endonuclease inhibitors as potential anti-toxicity drugs
Biography: Alexei G. Basnakian
Apoptotic endonucleases are the enzymes that universally induce irreversible cell death by fragmenting DNA in response to cell injury. While most of the DNase/endonuclease activity is used after cell death, the latest studies showed that genetic inactivation of some endonucleases provide protection of cells and tissues against DNA breaks induced by cytotoxic stimuli. These data suggest that DNases act before the “point of no return” in cell death, and display a possibility for new therapeutics aimed to inhibit endonucleases for tissue protection. However, inhibitors of apoptotic endonucleases are not available. We have developed several high throughput screening assays based on a proprietary fluorescent probe. This assays applied in solution allowed the identification of several new inhibitors of two apoptotic DNases, deoxyribonuclease I (DNase I) and endonucleases G (EndoG). The DNase inhibitors were able to partially protect kidney cells and mice from cisplatin toxicity. These or similar assays have a great promise as tools for new drug discovery.