CASPASE INHIBITORS

胱天蛋白酶抑制剂

• 批准号: 6525965
• 负责人: JAMES C POWERS
• 金额: $ 23.98万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6525965
• 关键词: apoptosis; combinatorial chemistry; cysteine endopeptidases; drug design /synthesis /production; enzyme activity; peptide library; protease inhibitor; proteolysis; tissue /cell culture

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.

细胞凋亡，也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、稳态和 多细胞生物的防御过度凋亡与 许多疾病状态，包括神经退行性疾病、中风、缺血性 损伤、获得性免疫缺陷综合征（艾滋病）、骨质疏松症和 肌萎缩侧索硬化症（ALS 0.细胞凋亡的启动导致 TNF或FAS配体与各种细胞表面受体的结合。信号 穿过细胞膜的转导导致半胱天冬酶的激活 从他们的专业人士。半胱氨酸蛋白酶是对天冬氨酸特异性的半胱氨酸蛋白酶 天然基质中的残留物。一种半胱天冬酶原被另一种半胱天冬酶原激活 半胱天冬酶导致蛋白水解级联反应，最终导致蛋白水解 在细胞凋亡中被选择性切割的关键蛋白质。目标 本研究的重点是设计和合成过渡态可逆和 半胱天冬酶，特别是半胱天冬酶-3， 6和8。肽α-酮酰胺抑制剂是过渡态抑制剂， 其通过与半胱氨酸蛋白酶形成四面体加合物来抑制半胱氨酸蛋白酶， 酶的活性位点半胱氨酸。我们建议合成特定的 半胱天冬酶的四肽抑制剂。一个新的类如果不可逆 将设计和合成对个体具有特异性的抑制剂， 半胱天冬酶我们建议开发用于制备不可逆聚合物文库的方法。 半胱天冬酶抑制剂。所有新的抑制剂都将进行效价测定， 所有可用的半胱天冬酶的特异性。最有效和最具体的 将在细胞凋亡测定中测试每种半胱天冬酶的抑制剂。很可能 半胱天冬酶抑制剂将具有治疗潜力， 中风和其他神经变性疾病。这项研究将提供 各种半胱天冬酶的活性位点结构的信息，并导致 设计更好的药物。