DESIGN OF PROTEASE INHIBITORS

拟议的研究涉及合成一些酶抑制剂， 评价它们的结合行为，以及这种结合的相关性 相关底物的周转行为。 我们的目的是发展 设计生物活性分子的有效策略 深入了解抑制剂结合和酶之间的关系 机制 在此过程中产生的抑制剂 工作应该在抗肿瘤治疗领域具有医学重要性， 高血压和镇痛。 该计划的关键要素是 以下内容： A.胞苷脱氨酶：磷酸嘧啶的立体选择性 将评价抑制剂，无论它们是否为过渡态类似物 将被确定，它们之间的关系缓慢结合， 将检查行为和蛋白质构象变化。 B。锌肽酶：磷酰胺与过渡的相关性 状态绑定将被扩展，这些慢绑定机制 抑制剂将被阐明，嗜热菌蛋白酶和羧肽酶A将被阐明。 在这方面进行比较，一类新的膦酰胺抑制剂将 被探索。 C.天冬氨酸肽酶：抑制的性质 将阐明含磷胃蛋白酶抑制剂类似物，解释 由于其缓慢的两步结合行为，将寻求膦酰胺， 和膦酸缓蚀剂将开发为更准确的 这类肽酶的过渡态类似物。 D.谷氨酰胺依赖性酰胺转移酶： 这些酶的抑制将被开发并应用于合成 氨甲酰磷酸合成酶的多底物类似物， 磷酸核糖焦磷酸酰胺转移酶。 E.腺苷脱氨酶：腺苷的次膦酸盐和膦酰胺类似物 共形霉素将被合成为四面体的更好的模拟物， 中间体，它们的抑制和缓慢结合将在 与酶的构象变化有关。 F.亚砜作为脱水酶抑制剂：自杀抑制剂研究计划 基于酶诱导的Pummerer型反应将被启动（酶 地址：肉毒碱乙酰转移酶，β-羟基癸酰基硫酯 脱氢酶和甲羟戊酸焦磷酸脱羧酶）。

The proposed research involves synthesis of a number of enzyme inhibitors, evaluation of their binding behavior, and correlation of this binding behavior with turnover of related substrates. Our intention is to develop effective strategies for the design of biologically active molecules and to provide insight into the relationship between inhibitor binding and enzyme mechanism. The inhibitors that are developed during the course of this work should be of medicinal importance in the areas of antitumor therapy, hypertension, and analgesia. The key elements to the program are the following: A. Cytidine Deaminase: The stereoselectivity of phosphapyrimidine inhibitors will be evaluated, whether they are transition state analogs will be determined, and the relationship between their slow-binding behavior and protein conformational changes will be examined. B. Zinc Peptidases: The correlation between phosphonamidate and transition state binding will be extended, the mechanism of slow-binding for these inhibitors will be elucidated, thermolysin and carboxypeptidase A will be compared in this respect, and a new class of phosphonamide inhibitors will be explored. C. Aspartic Peptidases: The nature of inhibition by a phosphorous-containing pepstatin analog will be elucidated, an explanation for its slow, two-step binding behavior will be sought, and phosphinamides and phosphonic acid inhibitors will be developed as more accurate transition state analogs for this class of peptidases. D. Glutamine-Dependent Amidotransferases: A general strategy for the inhibition of these enzymes will be developed and applied to the synthesis of multisubstrate analogs for carbamyl phosphate synthetase and phosphoribosyl pyrophosphate amidotransferase. E. Adenosine Deaminase: The phosphinate and phosphinamide analogs of coformycin will be synthesized as better mimics of the tetrahedral intermediate, their inhibition and slow-binding will be analyzed in relation to enzyme conformational changes. F. Sulfoxides as Inhibitors of Dehydrases: A program on suicide inhibitors based on enzyme-induced Pummerer-type reactions will be initiated (enzymes addressed: carnitine acetyltransferase, Beta-hydroxydecanoyl thiolester dehydrase, and mevalonate pyrophosphate decarboxylase).