CASPASE INHIBITORS

细胞凋亡，也被称为程序性细胞死亡，是一种正常的 生理性细胞死亡过程，对形态发生、动态平衡和 保卫多细胞生物体。过度的细胞凋亡与 多种疾病状态，包括神经退行性疾病、中风、缺血性 伤害、获得性免疫缺陷综合症(艾滋病)、骨质疏松症和 肌萎缩侧索硬化症(也称为0。启动细胞凋亡的结果是 肿瘤坏死因子或Fas配体与多种细胞表面受体的结合。讯号 跨细胞膜转导导致半胱氨酸氨基转移酶激活 从他们的正式表格上看。半胱氨酸蛋白酶是天冬氨酸特异性的半胱氨酸蛋白酶 天然底物中的残留物。一种原天冬氨酸酶被另一种原天冬氨酸酶激活 半胱氨酸氨基转移酶导致蛋白水解级联反应，最终导致蛋白分解。 已知的在细胞凋亡中选择性切割的关键蛋白。目标是 本研究的重点是设计和合成过渡态可逆和 Caspase，特别是caspase-3的不可逆机制抑制物， 6和8.多肽α-酮酰胺抑制剂是过渡态抑制剂， 它通过形成一个四面体，与半胱氨酸蛋白酶加合物来抑制半胱氨酸蛋白酶 酶的活性部位半胱氨酸。我们建议合成特定的 半胱氨酸天冬氨酸酶的四肽抑制剂。一个不可逆转的新类 抑制剂的设计和合成将针对不同的个体 半胱氨酸酶。我们建议开发制备不可逆库的方法 半胱氨酸酶抑制剂。将对所有新的抑制剂进行效力和 所有可用的半胱氨酸天冬氨酸酶的特异性。最有力和最具体的 每种半胱氨酸天冬氨酸酶的抑制剂将在细胞凋亡检测中进行测试。很有可能 半胱氨酸天冬氨酸氨基转移酶抑制剂将有治疗的潜力 中风和其他神经退行性疾病。这项研究应该提供 各种半胱氨酸天冬氨酸酶活性位点结构的信息，并导致 更好的药物的设计。

Apoptosis, also known as programmed cell death, is a normal physiological cell death process, essential for morphogenesis, homeostasis, and defense of multicellular organisms. Excessive apoptosis is associated with numerous disease states including neurodegenerative disorders, stroke, ischemic injuries, acquired immunodeficiency syndrome (AIDS), osteoporosis, and amyotrophic lateral sclerosis (ALS0. Initiation of apoptosis results upon binding of TNF or FAS ligand to various cell surface receptors. Signal transduction across the cell membrane results in the activation of caspases from their pro-forms. Caspases are cysteine proteases with specificity for Asp residues in their natural substrates. Activation of one procaspase by another caspase results in a proteolytic cascade, which eventually causes proteolysis of key proteins that are known to be selectively cleaved in apoptosis. The goal of this research is the design and synthesis of transition-state reversible and mechanism-based irreversible inhibitors for caspases, particularly caspase-3, 6, and 8. Peptide alpha-ketoamide inhibitors are transition-state inhibitors, which inhibit cysteine proteases by forming a tetrahedral, adduct with the active-site cysteine of the enzyme. We propose to synthesize specific tetrapeptide inhibitors for the caspases. A new class if irreversible inhibitors will be designed and synthesized with specificity for individual caspases. We propose to develop methods for preparing libraries of irreversible caspase inhibitors. All new inhibitors will be assayed for potency and specificity with all available caspases. The most potent and specific inhibitors for each caspase will be tested in apoptosis assays. It is likely that caspase inhibitors will have therapeutic potential for the treatment of stroke and other neurodegenerative diseases. This research should provide information of the active site structure of the various caspases and lead to the design of better drugs.