PLASMODIUM FALCIPARUM ASPARTIC PROTEINASE INHIBITOR DEVELOPMENT

恶性疟原虫天冬氨酸蛋白酶抑制剂的开发

• 批准号: 5205854
• 负责人: Daniel E. Goldberg
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5205854
• 关键词: Plasmodium falciparum; active sites; antimalarial agents; chemical kinetics; chemical models; chemical synthesis; computer simulation; drug design /synthesis /production; drug screening /evaluation; gene expression; inclusion body; laboratory mouse; nonhuman therapy evaluation; protease inhibitor; protein purification; recombinant proteins; site directed mutagenesis

The goal of the proposed research project is to understand at a molecular level and to inhibit the function of the aspartic hemoglobinase that initiates hemoglobin degradation in the human malaria parasite, Plasmodium falciparum. This organism causes disease in several hundred million people, death in millions of children each year, and is of concern to over one million travelers per year in this country alone. The parasite grows by catabolizing host erythrocyte hemoglobin and using the resulting amino acids as major nutrient source. We have shown that the initial enzyme in the catabolic pathway is an aspartic protease that makes a single cleavage to unravel the hemoglobin molecule, exposing it for further, efficient proteolysis. We have found a selective peptidomimetic inhibitor that blocks hemoglobinase action and kills P. falciparum parasites in culture. This protease appears to be a valid drug target. We now propose to examine in greater detail the properties of the enzyme and its interaction with inhibitors, using the tools of recombinant enzyme overexpression, molecular modeling, crystallography, and site-directed mutagenesis. Our goal is to better understand the structure and function of this important enzyme, as well as to improve the potency and selectivity of protease inhibition. The expertise of the other project groups in protein expression, molecular interactions and ultrastructural localization will be an enormous asset to this endeavor. It is expected that the proposed experiments will lead to the development of a serious drug candidate for the prophylaxis and treatment of malaria.

拟议研究项目的目标是了解一个分子 水平和抑制天冬氨酸血红蛋白酶的功能， 引发人类疟原虫血红蛋白的降解 恶性疟原虫。 这种微生物导致数亿人患病 每年有数百万儿童死亡， 每年光是这个国家就有一百万的游客 寄生虫会生长 通过分解代谢宿主红细胞血红蛋白并利用产生的氨基 酸是主要的营养来源。 我们已经证明， 分解代谢途径是天冬氨酸蛋白酶， 解开血红蛋白分子，使其暴露于更高的，有效的 蛋白水解 我们已经发现了一种选择性拟肽抑制剂， 阻断血红蛋白酶作用并杀死培养物中的恶性疟原虫寄生虫。 这种蛋白酶似乎是一个有效的药物靶点。 我们现在建议审查 更详细地描述了酶的性质及其与 抑制剂，使用重组酶过表达的工具，分子 建模、晶体学和定点诱变。 我们的目标是 更好地了解这种重要酶的结构和功能， 以及提高蛋白酶抑制的效力和选择性。 的 其他项目组在蛋白质表达、分子生物学、 相互作用和超微结构定位将是一个巨大的资产， 这种奋进。 预计拟议的实验将导致 开发用于预防的重要候选药物， 治疗疟疾。