PLASMODIUM FALCIPARUM ASPARTIC PROTEINASE INHIBITOR DEVELOPMENT
PLASMODIUM FALCIPARUM ASPARTIC PROTEINASE INHIBITOR DEVELOPMENT
批准号:
5205854
负责人:
Daniel E. Goldberg
金额:
$0.0万
依托单位:
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依托单位国家:
美国
项目类别:
财政年份:
--
资助国家:
美国
项目状态:
未结题
起止时间:
至
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
中文摘要
提出的研究项目的目标是在分子水平上理解
水平,并抑制天冬氨酸血红蛋白酶的功能
启动人类疟疾寄生虫疟原虫中的血红蛋白降解
恶性疟原虫。这种微生物导致数亿人患病。
每年有数以百万计的儿童死亡,这是人们关注的问题
仅在这个国家,每年就有100万游客。寄生虫不断生长
通过分解宿主红细胞血红蛋白并使用产生的氨基
酸是主要的营养来源。我们已经证明了体内的起始酶
分解代谢途径是一种天冬氨酸蛋白酶,它只进行一次裂解。
解开血红蛋白分子,让它更有效地暴露出来
蛋白质分解。我们已经发现了一种选择性的肽类抑制剂
阻断血红蛋白酶作用,杀死培养中的恶性疟原虫。
这种蛋白酶似乎是一个有效的药物靶点。我们现在建议研究一下
更详细地介绍了该酶的性质及其与
抑制剂,利用重组酶过表达的工具,分子
建模、结晶学和定点突变。我们的目标是
更好地了解这种重要酶的结构和功能,如
以及提高抑制蛋白水解酶的效力和选择性。这个
其他项目组在蛋白质表达、分子方面的专业知识
相互作用和超微结构本地化将是
这一努力。预计拟议的实验将导致
一种严重的预防和治疗候选药物的开发
疟疾的治疗。
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Specificity of Plasmodium falciparum protein export
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批准号:10632093
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项目类别:
-
资助金额:$19.46万
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财政年份:2022
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负责人:Daniel E. Goldberg
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依托单位:
Defining the resistome in P. falciparum: evolution and mechanism
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批准号:10608899
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项目类别:
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资助金额:$108.39万
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财政年份:2022
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负责人:Daniel E. Goldberg
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依托单位:
Specificity of Plasmodium falciparum protein export
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批准号:10508060
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项目类别:
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资助金额:$23.63万
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财政年份:2022
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负责人:Daniel E. Goldberg
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依托单位:
Structural Vaccinology and Design of Novel Imunogens for Malaria Vaccine Development
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批准号:10330551
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项目类别:
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资助金额:$71.36万
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财政年份:2018
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负责人:Daniel E. Goldberg
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依托单位:
Plasmepsin X function in Plasmodium
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批准号:10322714
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项目类别:
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资助金额:$38.13万
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财政年份:2018
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负责人:Daniel E. Goldberg
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依托单位:
Pathogenesis of HRPII in Cerebral Malaria
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批准号:9913445
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项目类别:
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资助金额:$38.13万
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财政年份:2016
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负责人:Daniel E. Goldberg
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依托单位:
Pathogenesis of HRPII in Cerebral Malaria
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批准号:9272362
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项目类别:
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资助金额:$38.13万
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财政年份:2016
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负责人:Daniel E. Goldberg
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依托单位:
IDENTIFICATION OF THE ANTIMALARIAL TARGET OF PEPSTATIN ESTERS
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批准号:8734676
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项目类别:
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资助金额:$37.02万
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财政年份:2014
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负责人:Daniel E. Goldberg
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依托单位:
ROLE OF PFHO-1 IN P. FALCIPARUM INTRAERYTHROCYTIC DEVELOPMENT
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批准号:8802857
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项目类别:
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资助金额:$22.88万
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财政年份:2014
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负责人:Daniel E. Goldberg
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依托单位:
ROLE OF PFHO-1 IN P. FALCIPARUM INTRAERYTHROCYTIC DEVELOPMENT
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批准号:8662416
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项目类别:
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资助金额:$17.94万
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财政年份:2014
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负责人:Daniel E. Goldberg
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依托单位:
IDENTIFICATION OF THE ANTIMALARIAL TARGET OF PEPSTATIN ESTERS
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批准号:8852545
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项目类别:
-
资助金额:$38.13万
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财政年份:2014
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负责人:Daniel E. Goldberg
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依托单位:
IDENTIFICATION OF THE ANTIMALARIAL TARGET OF PEPSTATIN ESTERS
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批准号:9285725
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项目类别:
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资助金额:$38.13万
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财政年份:2014
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负责人:Daniel E. Goldberg
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依托单位:
National Center for Environmental Health (NCEH) and The Agency for Toxic Substanc
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批准号:8235231
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项目类别:
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资助金额:$1.55万
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财政年份:2011
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负责人:Daniel E. Goldberg
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依托单位:
INFECTIOUS DISEASE/BASIC MICROBIAL PATHOGENIC MECHANISMS
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批准号:8168716
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项目类别:
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资助金额:$1.06万
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财政年份:2010
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负责人:Daniel E. Goldberg
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依托单位:
INFECTIOUS DISEASE/BASIC MICROBIAL PATHOGENIC MECHANISMS
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批准号:7953943
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项目类别:
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资助金额:$0.64万
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财政年份:2009
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负责人:Daniel E. Goldberg
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依托单位:
INFECTIOUS DISEASE/BASIC MICROBIAL PATHOGENIC MECHANISMS
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批准号:7721526
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项目类别:
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资助金额:$1.57万
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财政年份:2008
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负责人:Daniel E. Goldberg
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依托单位:
BIOLOGICAL ROLES OF PLASMEPSINS
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批准号:6374551
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项目类别:
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资助金额:$18.9万
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财政年份:2000
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负责人:Daniel E. Goldberg
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依托单位:
BIOLOGICAL ROLES OF PLASMEPSINS
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批准号:6157627
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项目类别:
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资助金额:$18.9万
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财政年份:2000
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负责人:Daniel E. Goldberg
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依托单位:
BIOLOGICAL ROLES OF PLASMEPSINS
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批准号:6741504
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项目类别:
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资助金额:$18.9万
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财政年份:2000
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负责人:Daniel E. Goldberg
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依托单位:
BIOLOGICAL ROLES OF PLASMEPSINS
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批准号:6608049
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项目类别:
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资助金额:$18.9万
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财政年份:2000
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负责人:Daniel E. Goldberg
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依托单位:
海外基金