Dysregulation of apoptosis has been shown to underlie the aetiology of many human diseases such as: cancer, viral infections, autoimmune diseases, neurodegenerative disorders, and AIDS. A key family of enzymes has been identified which interact with the death receptor, FAS, whose activation begins cellular apoptosis. Inhibition of these enzymes would suppress disease states due to excessive apoptosis, e.g. AIDS. This family of cysteine aspartyl proteases or caspases mediate a cascade type mechanism for the transmission of signals. Caspase-8 interacts directly with the FAS receptor and is the most upstream component of the cell death cascade. We propose a general strategy for regulation of cysteine proteases using a library of small molecule reversible inhibitors. A combinatorial library of small molecule inhibitors will be synthesized. As a proof of principle, the combinatorial array will be evaluated for activity against caspase-8 using a high throughput fluorometric assay. In addition, library synthesis will develop solid phase synthetic methods to access molecular functionality not readily amenable to previous solid phase methodology. Success of this approach with a particular enzyme target suggests broad application of this strategy to enzyme regulation with small molecules.
