Silanediols as Serine and Threonine Protease Inhibitors

描述（由申请人提供）：硅二醇是最近开发的水合羰基类似物，可作为金属和天冬氨酸蛋白酶的低纳摩尔抑制剂的有效构建块。丝氨酸蛋白酶也是关键的蛋白水解酶，其抑制剂具有广泛的治疗潜力。观察到硅二醇与甲醇进行了容易的、非催化的交换（最初用我们的HIV蛋白酶抑制剂观察到），表明它们也具有作为丝氨酸蛋白酶抑制剂的巨大潜力。我们将评估硅烷二醇作为丝氨酸和苏氨酸蛋白酶的抑制剂，研究五种酶。凝乳胰蛋白酶是一种基准和现成的丝氨酸蛋白酶，将使我们能够快速建立硅二醇作为丝氨酸蛋白酶抑制剂，包括x射线晶体学。乳糜酶是免疫反应的重要组成部分；目前对识别序列的理解将使我们能够快速开发抑制剂。组织蛋白酶G是一种参与组织重塑的酶，在特异性上与乳糜酶重叠，这将使我们能够评估硅二醇的特异性。颗粒酶B具有独特的PI识别要求，在细胞凋亡中起重要作用。20S蛋白酶体，一种苏氨酸蛋白酶，将测试硅二醇与这种重要但在空间上更受阻的亲核试剂相互作用的极限。除了凝乳胰蛋白酶外，所有靶点都与医学相关，硅烷二醇抑制作用将通过酶x射线晶体学进一步探索（与巴斯大学的K. R. Acharya合作）。

DESCRIPTION (provided by applicant): Silanediols are recently developed analogues of the hydrated carbonyl that are effective as building blocks for low nanomolar inhibitors of metallo- and aspartic proteases. Serine proteases are also critical proteolytic enzymes whose inhibitors have broad therapeutic potential. The observation that Silanediols undergo facile, uncatalyzed exchange with methanol (initially observed with our HIV protease inhibitor) indicates that they have great potential as serine protease inhibitors as well. We will evaluate silandiols as inhibitors of serine and threonine proteases, studying five enzymes. Chymotrypsin is a benchmark and readily available serine protease that will allow us to rapidly establish Silanediols as serine protease inhibitors, including X-ray crystallography. Chymase is an important part of the immune response; the current understanding of the recognition sequence will allow us to quickly develop inhibitors. Cathepsin G is an enzyme involved in tissue remodeling with an overlap in specificity with chymase that will allow us to assess silanediol specificity. Granzyme B has a unique PI recognition requirement and is important in apoptosis. The 20S proteasome, a threonine protease, will test the limits of the Silanediols to interact with this important but sterically more hindered nucleophile. All targets except chymotrypsin are medically relevant, and silanediol inhibition will be further explored with enzyme X-ray crystallography (in collaboration with K. R. Acharya, Univ. of Bath)