SILANOL INHIBITORS OF METALLOPROTEASE ENZYMES

金属蛋白酶的硅烷醇抑制剂

• 批准号: 6184641
• 负责人: Scott McNeill Sieburth
• 金额: $ 15.78万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6184641
• 关键词: ACE inhibitors; X ray crystallography; active sites; chemical synthesis; collagenase; combinatorial chemistry; diol; enzyme substrate; metalloendopeptidases; peptidyl dipeptidase A; protease inhibitor; silicon compounds; stereochemistry; thermolysin

Silanediol inhibits the metalloprotease angiotensin-converting enzyme (ACE; see: Sieburth, Nittoli, Mutahi, and Guo "Silanediols: A New Class of Potent Protease Inhibitors," Angew. Chem. Int. Ed. Engl. 1998, 37, 812-814.) The proposed research will fully characterize the inhibition of ACE with silanols by first preparing the isomers in enantiomerically pure form. The resulting inhibition data will allow the silanediols to be compared to benchmark ACE inhibitors. Inhibitors of thermolysin will be prepared for comparison with analogous phosphorus-based inhibitors of thermolysin, using both kinetic data and X-ray crystallography at the enzyme active site (in collaboration with Brian Matthews). Application of silanediols to current medicinal chemistry targets will focus initially on the matrix metalloproteases (MMPs, especially collagenase) using combinatorial methods to survey the structure-activity relationships with the silanediol inhibitor core. Inhibitors of the newly identified metalloprotease, anthrax lethal factor (LF) will also utilize combinatorial chemistry to identify the requirements for substrate recognition by LF, for which very little is known.

硅烷二醇抑制金属蛋白酶血管紧张素转换酶 （ACE；参见：Sieburth、Nittoli、Mutahi 和Guo“硅烷二醇：新一类 强效蛋白酶抑制剂”，Angew. Chem. Int. Ed. Engl. 1998, 37, 812-814。）拟议的研究将充分描述抑制作用 首先制备对映体异构体，用硅烷醇制备 ACE 纯粹的形式。 由此产生的抑制数据将使硅烷二醇能够 与基准 ACE 抑制剂进行比较。 嗜热菌蛋白酶抑制剂会 准备与类似的磷基抑制剂进行比较 嗜热菌蛋白酶，使用动力学数据和 X 射线晶体学 酶活性位点（与 Brian Matthews 合作）。 应用 硅烷二醇对当前药物化学目标的影响将集中在 最初作用于基质金属蛋白酶（MMP，尤其是胶原酶） 使用组合方法来调查结构-活性 与硅烷二醇抑制剂核心的关系。 抑制剂 新发现的金属蛋白酶、炭疽致死因子（LF）也将 利用组合化学来确定以下要求 通过 LF 进行底物识别，对此我们知之甚少。