Chemical synthesis and rationale design of novel peptide and nonpeptide based small molecule inhibitors of SKI-1

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Subtilisin Kexin Isozyme-1 (SKI-1) is an enzyme found within cellular compartments of various tissues of mammalian systems, including human. This enzyme cuts larger, inactive protein molecules at specificpositions, to generate functionally active smaller protein forms that play important roles in various health conditions and diseases, including viral infections and cholesterol synthesis. In all cases, an increase of enzyme activity causes the formation of a higher level of biologically active cleaved product that eventually contributes to the initiation or progression of the disease. Therefore, one way of managing the disease will be to lower theactivity of the enzyme via the application of compounds or agents that interact or bind with the enzyme, thereby blocking its activity. In fact this approach has been applied for intervention of many diseases including hypertension, arthritis, asthma and AIDS. For more than a decade, our laboratory has been studying the structure, function and activity of several enzymes, including SKI-1. In this proposal we would like to make compounds that are capable of destroying or inhibiting the ability of the SKI-1 enzyme to cut inactive large proteins to their small functionally active forms. Thus, we will prepare several molecules based on various strategies with appropriate geometry so that they can bind to SKI-1 and make it less efficient in cutting large proteins. In theory these chemical compounds will find important applications, not only to study the function and mechanism of action of SKI-1 enzyme, but also as possible therapeutic agents. This research will therefore contribute to a better understanding of the importance of SKI-1 in certain diseases and could lead to novel lead compounds with important therapeutic values.