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

枯草杆菌毒素可信同工酶-1(SKI-1)是一种存在于包括人类在内的哺乳动物系统各种组织的细胞室中的酶。这种酶在特定位置切割较大的、不活跃的蛋白质分子，产生功能活跃的较小蛋白质形式，在各种健康状况和疾病中发挥重要作用，包括病毒感染和胆固醇合成。在所有情况下，酶活性的增加会导致形成更高水平的生物活性裂解产物，最终导致疾病的开始或进展。因此，控制疾病的一种方法是通过应用与酶相互作用或结合的化合物或试剂来降低酶的活性，从而阻止其活性。事实上，这种方法已经被应用于许多疾病的干预，包括高血压、关节炎、哮喘和艾滋病。十多年来，我们实验室一直在研究包括SKI-1在内的几种酶的结构、功能和活性。在这项提议中，我们想要制造能够破坏或抑制SKI-1酶将失活的大蛋白切割成具有功能活性的小形式的能力的化合物。因此，我们将根据不同的策略准备几个具有合适几何构型的分子，以便它们可以与SKI-1结合，从而降低其切割大型蛋白质的效率。从理论上讲，这些化合物将得到重要的应用，不仅可以研究SKI-1酶的功能和作用机制，还可以作为可能的治疗药物。因此，这项研究将有助于更好地了解SKI-1在某些疾病中的重要性，并可能导致具有重要治疗价值的新的先导化合物。

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.