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（由申请人提供）：硅烷二醇最近开发了水合羰基的类似物，它们是金属和天冬氨酸蛋白酶低纳摩尔抑制剂的构件有效的。丝氨酸蛋白酶也是抑制剂具有广泛治疗潜力的关键蛋白水解酶。关于硅烷二醇与甲醇（最初用我们的HIV蛋白酶抑制剂观察到的）进行的，无催化的交换的观察结果表明，它们作为丝氨酸蛋白酶抑制剂也具有很大的潜力。我们将评估silandiols作为丝氨酸和苏氨酸蛋白酶的抑制剂，研究五种酶。胰凝乳蛋白酶是一种基准且容易获得的丝氨酸蛋白酶，它将使我们能够迅速建立硅氧二醇作为丝氨酸蛋白酶抑制剂，包括X射线晶体学。芝麻酶是免疫反应的重要组成部分。当前对识别顺序的理解将使我们能够快速发展抑制剂。组织蛋白酶G是一种酶，参与组织重塑的酶与Chymase的特异性重叠，这将使我们能够评估硅二醇特异性。 Granzyme B具有独特的PI识别要求，在凋亡中很重要。 20S蛋白酶体是一种苏氨酸蛋白酶，将测试硅烷聚集二醇的极限，以与这种重要但更具障碍的亲核试剂相互作用。除胰凝乳蛋白酶以外的所有靶标在医学上都是相关的，并且将使用酶X射线晶体学进一步探索硅二醇抑制（与BATH的K. R. Acharya合作）