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

点击翻译按钮获取中文摘要

Subtilisin Kexin Isozyme-1 (SKI-1) also known as Site1Protease (S1P) is a proteolytic enzyme found within cellular compartments of various tissues of mammalian systems, including human. This enzyme cleaves larger, inactive protein molecules at specific sites, 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 in enzyme activity of SKI-1 results in the formation of a higher level of biologically active cleaved product/s that eventually contribute to the initiation or progression of the disease. One way of managing the disease will be to lower down the activity of the enzyme via the application of chemical agents that interact and bind with the enzyme, thereby blocking its activity. In fact this approach has been applied for intervention of many diseases including cardiovascular diseases, hypertension, arthritis, asthma and AIDS. For more than a decade, our laboratory has been engaged in studying structure, function and activity of several enzymes including SKI-1. In this proposal we intend to develop compounds that are capable of inhibiting the ability of the SKI-1 enzyme to cleave large inactive proteins to their small functionally active forms. Thus, we will prepare several SKI-1 inhibitory compounds based on various strategies which can inactivate SKI-1 and make it less efficient in cutting large proteins. In theory these compounds are expected to find important applications, not only to study the function of the enzyme, but also in therapeutic interventions of diseases such as viral infections, hypercholesterolemia etc. This research will therefore contribute to a better understanding of the importance of SKI-1 in above diseases and could lead to novel compounds with important therapeutic values.