Silanediols as Serine and Threonine Protease Inhibitors

硅烷二醇作为丝氨酸和苏氨酸蛋白酶抑制剂

• 批准号: 7148986
• 负责人: Scott McNeill Sieburth
• 金额: $ 27.47万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7148986
• 关键词: X ray crystallography; cathepsin G; chymase; chymotrypsin; cytotoxic T lymphocyte; diol; endopeptidases; enzyme mechanism; protease inhibitor; proteasome; serine; silanes; threonine

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)

描述(申请人提供)：硅二醇是最近开发的水合羰基的类似物，有效地作为金属和天冬氨酸蛋白酶的低纳米分子抑制剂的构建块。丝氨酸蛋白酶也是一种关键的蛋白水解酶，其抑制剂具有广泛的治疗潜力。观察到硅烷二醇与甲醇进行了简单的、非催化的交换(最初是用我们的HIV蛋白酶抑制剂观察到的)，这表明它们作为丝氨酸酶抑制剂也有很大的潜力。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。糜蛋白酶是一种基准的和容易获得的丝氨酸蛋白酶，它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射线结晶学。糜酶是免疫反应的重要组成部分；目前对识别序列的了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，其特异性与糜酶有重叠，这将使我们能够评估硅烷二醇的特异性。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蛋白酶体是一种苏氨酸蛋白酶，它将测试硅烷二醇与这种重要但更具毒性的亲核试剂相互作用的极限。除胰凝乳酶外的所有靶点都与医学有关，将用酶X射线结晶学进一步探索硅二醇的抑制作用(与K.R.Acharya大学合作)。(Bath)