HEMOGLOBIN CATABOLISM BY PLASMODIUM FALCIPARUM

恶性疟原虫的血红蛋白分解代谢

• 批准号: 2065832
• 负责人: ANTHONY CERAMI
• 金额: $ 21.67万
• 依托单位: PICOWER INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-06-01 至 1996-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2065832
• 关键词: Plasmodium falciparum; SDS polyacrylamide gel electrophoresis; antimalarial agents; density gradient ultracentrifugation; drug design /synthesis /production; electron spin resonance spectroscopy; endopeptidases; enzyme mechanism; genetic manipulation; hemoglobin; hemoprotein metabolism; hemoprotein structure; high performance liquid chromatography; immunoprecipitation; malaria; molecular cloning; nucleic acid probes; parasitic disease chemotherapy; protease inhibitor; protein sequence

Malaria remains the most prevalent and devastating parasitic disease of the tropics. It is indigenous in over one hundred countries or areas of the world; over 50 % of the world's human population reside in areas endemic for this disease. Over the last 30 years the battle to contain malaria has swung towards the parasite with the emergence and gradual spread of drug-resistant organisms. Multi-drug resistant Plasmodium falciparum, the most deadly species of malaria infection, has been identified throughout Africa, Asia and South America and is spreading rapidly. There is a desperate need for new therapies. This project is directed towards a fundamental understanding of a key area of P. falciparum biochemistry - the process of intraerythrocytic hemoglobin catabolism, which is shown to be an excellent but largely uncharacterized target for chemotherapy. The long term objective of the research is to design novel and specific chemotherapeutic agents which perturb this area of parasite metabolism. The primary aims of this project are: Firstly, to carry out mechanistic and structural characterization of a novel aspartic hemoglobin protease which is present in the lysosomal vacuole of P. falciparum and to develop specific inhibitors of its function. Secondly, to determine the mechanism of biosynthesis of malaria pigment (hemozoin) which is the end product of parasite induced hemoglobin catabolism. These problems are tackled in a multidisciplinary approach which includes the technology of physical and structural chemistry, biochemistry and molecular biology.

疟疾仍然是最普遍和最具破坏性的寄生虫病， 热带病。 它是一百多个国家的本土植物 世界上超过50%的人口居住在 在这种疾病流行的地区。 在过去的30年里， 随着疟疾的出现， 耐药微生物的逐渐扩散。 耐多药 恶性疟原虫是最致命的疟疾感染种类， 在非洲、亚洲和南美洲都有发现， 迅速蔓延。 迫切需要新的疗法。 本项目旨在从根本上了解 恶性疟原虫生物化学的关键领域-红细胞内 血红蛋白催化剂，这是一个很好的，但很大程度上是 未表征的化疗靶点。 的长远目标 研究是设计新的和特异性的化疗剂， 扰乱寄生虫代谢的这一区域。 该项目的主要目标是：首先， 一种新型天冬氨酸衍生物的合成机理和结构表征 血红蛋白蛋白酶存在于P. 恶性疟原虫，并开发其功能的特异性抑制剂。 第二、 探讨疟原虫色素（疟原虫色素）的生物合成机制 其是寄生虫诱导的血红蛋白催化剂的终产物。 这些问题是以多学科方法处理的，其中包括 物理和结构化学、生物化学和 分子生物学