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

枯草杆菌蛋白酶Kexin同工酶-1（SKI-1）也称为Site 1蛋白酶（S1 P），是在哺乳动物系统（包括人类）的各种组织的细胞区室中发现的蛋白水解酶。这种酶在特定位点切割较大的无活性蛋白质分子，产生功能活性较小的蛋白质形式，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，SKI-1的酶活性增加导致形成更高水平的生物活性切割产物，其最终有助于疾病的起始或进展。控制疾病的一种方法是通过应用与酶相互作用并结合的化学试剂来降低酶的活性，从而阻断其活性。事实上，这种方法已被应用于许多疾病的干预，包括心血管疾病，高血压，关节炎，哮喘和艾滋病。十多年来，本实验室一直从事包括SKI-1在内的多种酶的结构、功能和活性的研究。在该提案中，我们打算开发能够抑制SKI-1酶将大的无活性蛋白质切割成其小的功能活性形式的能力的化合物。因此，我们将基于各种策略制备几种SKI-1抑制化合物，这些化合物可以抑制SKI-1并使其在切割大蛋白质时效率降低。在理论上，这些化合物有望找到重要的应用，不仅研究酶的功能，而且在疾病的治疗干预，如病毒感染，高胆固醇血症等，因此，这项研究将有助于更好地了解SKI-1在上述疾病中的重要性，并可能导致具有重要治疗价值的新化合物。

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.