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.

硅二二醇抑制金属蛋白酶血管紧张素转化酶 （ACE；见：Sieburth，Nittoli，Mutahi和Guo“ Silanediols：新课程 有效蛋白酶抑制剂，“ Angew。Chem。Int。Engl。1998，37， 812-814。）拟议的研究将充分表征抑制作用 通过首先准备对映异构体中的异构体的王牌与硅烷酚 纯形。 由此产生的抑制数据将使硅氧二醇能够 将其与基准ACE抑制剂进行比较。 热蛋白的抑制剂将 准备与基于类似磷的抑制剂进行比较 热素，使用动力学数据和X射线晶体学处 酶为活性站点（与Brian Matthews合作）。 应用 将硅氧二醇用于当前的药物化学靶标的 最初在基质金属蛋白酶（MMP，尤其是胶原酶）上 使用组合方法调查结构活性 与硅烷二醇抑制剂核心的关系。 抑制剂 新确定的金属蛋白酶，炭疽致死因素（LF）也将 利用组合化学来确定 LF识别的底物识别，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