SILANOL INHIBITORS OF METALLOPROTEASE ENZYMES

金属蛋白酶的硅烷醇抑制剂

• 批准号: 6390302
• 负责人: Scott McNeill Sieburth
• 金额: $ 16.25万
• 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 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390302
• 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“Siladiols：A New Class 蛋白酶抑制剂，”Angew。化学国际教育英语1998年，37， 812-814.） 拟议的研究将充分表征抑制 通过首先制备对映异构体， 纯粹的形式。 所得抑制数据将允许硅烷二醇 与基准ACE抑制剂进行比较。 嗜热菌蛋白酶的抑制剂将 准备与类似的磷基抑制剂进行比较 的嗜热菌蛋白酶，同时使用动力学数据和X射线晶体学在 酶活性位点（与Brian马修斯合作）。 应用 目前的药物化学目标的硅烷二醇将集中 最初对基质金属蛋白酶（MMPs，特别是胶原酶） 用组合方法研究构效关系 与硅烷二醇抑制剂核心的关系。 的抑制剂 一种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 LF的底物识别，对此知之甚少。

项目成果

Structural analysis of silanediols as transition-state-analogue inhibitors of the benchmark metalloprotease thermolysin.

硅烷二醇作为基准金属蛋白酶嗜热菌蛋白酶过渡态类似物抑制剂的结构分析。

• DOI: 10.1021/bi051346v
• 发表时间: 2005
• 期刊: Biochemistry.
• 作者: Juers,DouglasH;Kim,Jaeseung;Matthews,BrianW;Sieburth,ScottMcN
• 通讯作者: Sieburth,ScottMcN