HEMOGLOBIN CATABOLISM BY PLASMODIUM FALCIPARUM

恶性疟原虫的血红蛋白分解代谢

• 批准号: 3145749
• 负责人: ANTHONY CERAMI
• 金额: $ 17.32万
• 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/3145749
• 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.

疟疾仍然是最流行和最具破坏性的寄生虫 热带疾病。它原产于一百多个国家。 或世界各地；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， 随着疟疾的出现和流行，遏制疟疾已经转向寄生虫 抗药性生物体的逐渐传播。多药耐药 恶性疟原虫是感染疟疾的最致命物种，它有 在非洲、亚洲和南美洲都被发现，并且是 迅速蔓延。人们迫切需要新的治疗方法。 本项目旨在从根本上理解 恶性疟原虫生化的关键区域--红细胞内过程 血红蛋白分解代谢，这被证明是一个很好的，但很大程度上 未确定的化疗靶点。该计划的长远目标 研究是设计新的和特定的化疗药物， 扰乱这一区域的寄生虫新陈代谢。 该项目的主要目标是：第一，开展 一种新型天冬氨酸的机理和结构表征 溶酶体液泡中存在的血红蛋白水解酶。 恶性疟原虫，并开发其功能的特异性抑制剂。第二， 确定疟疾色素(血球蛋白)的生物合成机制 它是寄生虫诱导的血红蛋白分解代谢的最终产物。 这些问题是通过多学科方法解决的，其中包括 物理化学和结构化学、生物化学和生物化学技术 分子生物学。