SILANOL INHIBITORS OF METALLOPROTEASE ENZYMES

硅二醇抑制金属蛋白酶血管紧张素转换酶 (王牌；见：Sieburth，Nittoli，Mutahi和Guo“Silandiol：一个新的类别” Of Powerent Protease Inhibitors，“Angew.Chem.Inc.Ed.Eng.1998，37， 812-814。)拟议的研究将充分描述这种抑制的特征 先对映异构体制备ACE与硅烷醇的反应 纯粹的形式。由此产生的抑制数据将允许硅烷二醇 与基准血管紧张素转换酶抑制剂相比。热裂解酶抑制剂将 准备与类似的磷基缓蚀剂进行比较 利用动力学数据和X-射线结晶学在 酶活性站点(与Brian Matthews合作)。应用 将重点关注硅烷二醇对当前药物化学目标的影响 最初对基质金属蛋白酶(MMPs，尤其是胶原酶)的研究 用组合方法研究构效关系 与硅烷二醇抑制剂核心的关系。血管紧张素转换酶抑制剂 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 LF对底物的识别，人们对此知之甚少。

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.