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

基本信息

批准号：
7489356
负责人：
Scott McNeill Sieburth
金额：
$ 25.46万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
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/7489356
关键词：
Active Sites Address Alcohol consumption Amides Amino Acids Angiotensins Apoptosis Aspartic Acid Aspartic Endopeptidases Asthma Bathing Benchmarking Binding Cathepsin G Chemistry Chymase Collaborations Complex Crystallography Disease Drug Delivery Systems Endopeptidases Enzymatic Biochemistry Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Generations Goals HIV Protease Inhibitors Hydrolysis Hydroxyl Radical Immune response Individual Ketones Letters Malignant Neoplasms Metalloproteases Methanol Object Attachment Oxygen Peptide Hydrolases Peptides Pharmaceutical Chemistry Pharmacologic Substance Play Positioning Attribute Principal Investigator Protease Inhibitor Proteasome Inhibition Research Resources Rheumatoid Arthritis Role Serine Serine Protease Serine Proteinase Inhibitors Side Silanes Silicon Site Specificity Stroke Structure Testing Therapeutic Threonine Tissues Ubiquitin-mediated Proteolysis Pathway Universities Water X-Ray Crystallography analog base carbonyl group chymotrypsin chymotrypsin-like enzyme design enzyme structure granzyme B hydroxyl group inhibitor/antagonist interest mast cell multicatalytic endopeptidase complex preference professor programs protein aminoacid sequence response silane silanediol tool

项目摘要

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）：硅烷二醇是最近开发的水合羰基类似物，可有效作为金属蛋白酶和天冬氨酸蛋白酶的低纳摩尔抑制剂的构建模块。丝氨酸蛋白酶也是重要的蛋白水解酶，其抑制剂具有广泛的治疗潜力。硅烷二醇与甲醇进行轻松、无催化的交换（最初在我们的 HIV 蛋白酶抑制剂中观察到）的观察表明，它们作为丝氨酸蛋白酶抑制剂也具有巨大的潜力。我们将评估硅二醇作为丝氨酸和苏氨酸蛋白酶抑制剂的作用，研究五种酶。胰凝乳蛋白酶是一种基准且易于获得的丝氨酸蛋白酶，它将使我们能够快速确定硅烷二醇作为丝氨酸蛋白酶抑制剂，包括 X 射线晶体学。食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，其特异性与食糜酶重叠，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，在细胞凋亡中很重要。 20S 蛋白酶体是一种苏氨酸蛋白酶，将测试硅烷二醇与这种重要但空间位阻更大的亲核试剂相互作用的极限。除胰凝乳蛋白酶外的所有目标均具有医学相关性，并且将通过酶 X 射线晶体学进一步探讨硅烷二醇的抑制作用（与巴斯大学 K. R. Acharya 合作）