Plasmepsin X function in Plasmodium

Plasmodium 中 Plasmepsin X 的功能

基本信息

  • 批准号:
    10322714
  • 负责人:
  • 金额:
    $ 38.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-01-02 至 2023-12-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY / ABSTRACT Malaria afflicts several hundred million and kills more than 600,000 people each year, mostly children in Sub-Saharan Africa. Aspartic proteases have long been antimalarial targets of interest. A large number of aspartic protease inhibitors that are potent against parasites in culture have been developed, but their specific targets have been elusive. Plasmepsin X (PMX) is one of the least characterized aspartic proteases found in asexual intraerythrocytic malaria parasites. We have recently found that PMX is a key enzyme for intraerythrocytic parasite egress and invasion. It activates the master trigger subtilysin-like protease 1 (SUB1), launching proteolytic events that allow merozoites to get out of the host red blood cell (RBC) and invade fresh RBCs. We have identified a class of aspartic protease inhibitors called aminohydantoins that appear to kill parasites through PMX blockade, preventing SUB1 activation and impairing egress/invasion. PMX knockdown phenocopies inhibitor action. One of the inhibitors has favorable pharmacokinetic properties and gives oral cure in a rodent malaria model. We believe that PMX is an exciting new drug target but need to better characterize its function to inform ongoing drug development and enhance our understanding of parasite biology. To address these questions, aim 1 will examine the specificity of PMX and will address the question of whether SUB1 maturation by PMX is direct. Biochemical assays using isolated PMX with SUB1 as a substrate and with a random peptide library will be performed. Aim 2 will focus on what PMX interacts with. Is SUB1 the only substrate? What else is in the secretory vesicle called the exoneme, where PMX and SUB1 both reside? Aim 3 will address the question of how PMX itself gets activated. Our preliminary data suggest that there must be an upstream enzyme. We will characterize the processing and look for a maturase. We anticipate that the proposed studies will yield great insight into the pathogenesis of malaria and will point the way to new therapies for this devastating disease.
项目摘要/摘要

项目成果

期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Maturation and substrate processing topography of the Plasmodium falciparum invasion/egress protease plasmepsin X.
  • DOI:
    10.1038/s41467-022-32271-7
  • 发表时间:
    2022-08-04
  • 期刊:
  • 影响因子:
    16.6
  • 作者:
    Mukherjee, Sumit;Nguyen, Suong;Sharma, Eashan;Goldberg, Daniel E.
  • 通讯作者:
    Goldberg, Daniel E.
Activation of the Plasmodium Egress Effector Subtilisin-Like Protease 1 Is Mediated by Plasmepsin X Destruction of the Prodomain.
  • DOI:
    10.1128/mbio.00673-23
  • 发表时间:
    2023-04-25
  • 期刊:
  • 影响因子:
    6.4
  • 作者:
    Mukherjee, Sumit;Nasamu, Armiyaw S.;Rubiano, Kelly C.;Goldberg, Daniel E.
  • 通讯作者:
    Goldberg, Daniel E.
Rounding precedes rupture and breakdown of vacuolar membranes minutes before malaria parasite egress from erythrocytes.
  • DOI:
    10.1111/cmi.12868
  • 发表时间:
    2018-10
  • 期刊:
  • 影响因子:
    3.4
  • 作者:
    Glushakova S;Beck JR;Garten M;Busse BL;Nasamu AS;Tenkova-Heuser T;Heuser J;Goldberg DE;Zimmerberg J
  • 通讯作者:
    Zimmerberg J
Fast-Acting Small Molecules Targeting Malarial Aspartyl Proteases, Plasmepsins, Inhibit Malaria Infection at Multiple Life Stages.
针对疟疾天冬氨酰蛋白酶、纤溶酶的速效小分子可抑制多个生命阶段的疟疾感染。
  • DOI:
    10.1021/acsinfecdis.8b00197
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    5.3
  • 作者:
    Singh,Snigdha;Rajendran,Vinoth;He,Jiang;Singh,AmitK;Achieng,AngelaO;Vandana;Pant,Akansha;Nasamu,ArmiyawS;Pandit,Mansi;Singh,Jyoti;Quadiri,Afshana;Gupta,Nikesh;Poonam;Ghosh,PrahladC;Singh,BrajendraK;Narayanan,Latha;Kempai
  • 通讯作者:
    Kempai
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Daniel E. Goldberg其他文献

Characterization of Membrane Contact Sites for the Facilitation of Lipid Exchange at the Malaria Parasite - Red Blood Cell Interface
  • DOI:
    10.1016/j.bpj.2019.11.3119
  • 发表时间:
    2020-02-07
  • 期刊:
  • 影响因子:
  • 作者:
    Matthias Garten;Josh Beck;Robyn Roth;John E. Heuser;Tatyana Tenkova-Heuser;Christopher K.E. Bleck;Daniel E. Goldberg;Joshua Zimmerberg
  • 通讯作者:
    Joshua Zimmerberg
The structure of Ascaris hemoglobin domain I at 2.2 A resolution: molecular features of oxygen avidity.
2.2 A 分辨率下蛔虫血红蛋白结构域 I 的结构:氧亲合力的分子特征。
When the Host Is Smarter Than the Parasite
当宿主比寄生虫更聪明时
  • DOI:
  • 发表时间:
    2002
  • 期刊:
  • 影响因子:
    56.9
  • 作者:
    Daniel E. Goldberg
  • 通讯作者:
    Daniel E. Goldberg
Malaria parasites require a divergent heme oxygenase for apicoplast gene expression and biogenesis
疟疾寄生虫需要不同的血红素加氧酶来进行顶质体基因表达和生物合成
  • DOI:
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Amanda Mixon Blackwell;Y. Jami;Armiyaw S. Nasamu;S. Kudo;A. Senoo;Celine Slam;Kouhei Tsumoto;James A. Wohlschlegel;J. Caaveiro;Daniel E. Goldberg;P. Sigala
  • 通讯作者:
    P. Sigala
ColE1 hybrid plasmids for Escherichia coli genes of glycolysis and the hexose monophosphate shunt
用于大肠杆菌糖酵解和己糖单磷酸分流基因的 ColE1 杂交质粒
  • DOI:
    10.1128/jb.137.1.502-506.1979
  • 发表时间:
    1979
  • 期刊:
  • 影响因子:
    3.2
  • 作者:
    Jennifer Thomson;T. P. D. Gerstenberger;Daniel E. Goldberg;Eva Gociar;Arminda Orozco DE Silva;D. Fraenkel
  • 通讯作者:
    D. Fraenkel

Daniel E. Goldberg的其他文献

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{{ truncateString('Daniel E. Goldberg', 18)}}的其他基金

Specificity of Plasmodium falciparum protein export
恶性疟原虫蛋白输出的特异性
  • 批准号:
    10632093
  • 财政年份:
    2022
  • 资助金额:
    $ 38.13万
  • 项目类别:
Defining the resistome in P. falciparum: evolution and mechanism
恶性疟原虫抗性组的定义:进化和机制
  • 批准号:
    10608899
  • 财政年份:
    2022
  • 资助金额:
    $ 38.13万
  • 项目类别:
Specificity of Plasmodium falciparum protein export
恶性疟原虫蛋白输出的特异性
  • 批准号:
    10508060
  • 财政年份:
    2022
  • 资助金额:
    $ 38.13万
  • 项目类别:
Structural Vaccinology and Design of Novel Imunogens for Malaria Vaccine Development
用于疟疾疫苗开发的结构疫苗学和新型免疫原设计
  • 批准号:
    10330551
  • 财政年份:
    2018
  • 资助金额:
    $ 38.13万
  • 项目类别:
Pathogenesis of HRPII in Cerebral Malaria
HRPII 在脑型疟疾中的发病机制
  • 批准号:
    9913445
  • 财政年份:
    2016
  • 资助金额:
    $ 38.13万
  • 项目类别:
Pathogenesis of HRPII in Cerebral Malaria
HRPII 在脑型疟疾中的发病机制
  • 批准号:
    9272362
  • 财政年份:
    2016
  • 资助金额:
    $ 38.13万
  • 项目类别:
IDENTIFICATION OF THE ANTIMALARIAL TARGET OF PEPSTATIN ESTERS
胃酶抑素酯抗疟靶点的鉴定
  • 批准号:
    8734676
  • 财政年份:
    2014
  • 资助金额:
    $ 38.13万
  • 项目类别:
ROLE OF PFHO-1 IN P. FALCIPARUM INTRAERYTHROCYTIC DEVELOPMENT
PFHO-1 在恶性疟原虫红细胞内发育中的作用
  • 批准号:
    8802857
  • 财政年份:
    2014
  • 资助金额:
    $ 38.13万
  • 项目类别:
ROLE OF PFHO-1 IN P. FALCIPARUM INTRAERYTHROCYTIC DEVELOPMENT
PFHO-1 在恶性疟原虫红细胞内发育中的作用
  • 批准号:
    8662416
  • 财政年份:
    2014
  • 资助金额:
    $ 38.13万
  • 项目类别:
IDENTIFICATION OF THE ANTIMALARIAL TARGET OF PEPSTATIN ESTERS
胃酶抑素酯抗疟靶点的鉴定
  • 批准号:
    8852545
  • 财政年份:
    2014
  • 资助金额:
    $ 38.13万
  • 项目类别:

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    66B2956
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    1966
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