Apoptosis is the mechanisms of physiologic cell death that functions to maintain homeostasis under normal conditions. However, in certain diseases and following some types of tissue injury, this process becomes deregulated and an excessive rate of apoptosis contributes to the pathology. Current evidence indicates the mechanism of apoptosis involves a proteolytic cascade. A novel serine protease termed AP24 is postulated to transmit apoptotic signals from the cytosol to the nucleus resulting in DNA fragmentation. The primary goal of this proposal is to identify novel AP24 inhibitors with therapeutic potential. Synthetic combinatorial libraries will be screened in vitro for inhibition of AP24 proteolytic activity on synthetic substrates as well as isolated nuclei. The active drug species will be analyzed by recursive deconvulation technology. The best inhibitor(s) will be further evaluated for inhibition of apoptosis in whole cells and tested for toxicity. The results of these studies should identify potential drug candidates that may be useful for treatment of a variety of conditions that involve patho-apoptosis.
