Small molecule protein-glycan inhib. as malaria transmission-blocking therapuetic

小分子蛋白聚糖抑制。

基本信息

  • 批准号:
    8237055
  • 负责人:
  • 金额:
    $ 40.18万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-04-22 至 2014-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Malaria transmission entails development of the Plasmodium parasite in the mosquito. We have identified a critical interaction between an unknown ookinete lectin-like protein and a chondroitin sulfate glycosaminoglycan ligand on the mosquito midgut lumenal surface. We hypothesize that by disrupting this interaction through the use of small molecule inhibitors we can prevent parasite establishment in the mosquito and, subsequently, completely abrogate malaria transmission. This is a translational research grant proposal with the goal of taking our basic research understanding of Plasmodium-mosquito host interactions toward the development of novel highly potent malaria transmission-blocking therapeutics. Our first aim, the Complete molecular characterization of Plasmodium ookinete protein-midgut glycosaminoglycan interactions involves (1) identifying novel lectin-like ookinete molecules by glycan-affinity chromatography and mass spectrometry, (2) characterizing their functional role in vivo through the production of gene knockout parasites, (3) assessing their binding affinity for mosquito chondroitin glycosaminoglycans by protein array-surface plasmon resonance, and (3) gaining insight into the structure-function of the molecule(s) in complex with chondroitin glycosaminoglycan fragments and structural analogues by molecular modeling and x-ray crystallography. The second aim of the project, the Development of lead Plasmodium transmission-blocking glycan-mimetic compounds and assessment of their transmission-blocking potential involves identification of novel derivatives and analogues of our lead transmission-blocking compound, VS1 (a non-peptidyl polyvinylsulfonated polymer), which is a structural mimic of midgut chondroitin glycosaminoglycans and inhibits >95% of parasite development in the mosquito. To develop more potent structural analogs, we propose a four-tiered approach: (1) isolation of varying chain-lengths of the VS1 polymer, (2) derivitization of VS1 to enhance inhibitory activity and bioavailability, (3) derivitization of (+)-usnic acid, a polyphenolic compound from lichens, and (4) assessment of the utility of peptide mimotopes of mosquito chondroitin sulfate glycosaminoglycans as transmission-blocking vaccine targets. To help progress toward preclinical studies, the top candidate compounds from each approach will be analyzed for their pharmacokinetic and pharmacodynamic properties in animal and human serum models. Mosquitoes transmit the Plasmodium parasite from infected human hosts to uninfected individuals. By blocking a critical protein-glycan (carbohydrate) interaction between the parasite and the mosquito vector through the use of small inhibitory compounds (drugs) we prevent parasite establishment in the mosquito and effectively disrupt the transmission cycle of the malaria parasite. This strategy is especially important given that many current antimalarials and vaccine candidates still permit transmission of the parasite through the mosquito, moreover, our lead compound has added potential utility as a multi-stage antimalarial therapeutic since it also prevents sporozoite establishment in liver cells, the first step towards the progression of disease in humans.
说明(由申请人提供):疟疾传播需要蚊子体内疟原虫的发展。我们已经确定了蚊子中肠管表面未知的卵泡细胞凝集素样蛋白和硫酸软骨素糖胺聚糖配体之间的关键相互作用。我们假设,通过使用小分子抑制剂破坏这种相互作用,我们可以防止寄生虫在蚊子体内建立,随后,完全废除疟疾传播。这是一项转化研究拨款提案,其目标是将我们对疟原虫-蚊子宿主相互作用的基本研究理解用于开发新型高效疟疾传播阻断疗法。我们的第一个目标,疟原虫卵胞体蛋白-中肠糖胺聚糖相互作用的完整分子表征包括:(1)通过聚糖亲和色谱和质谱鉴定新的凝集素样卵胞体分子,(2)通过产生基因敲除寄生虫来表征它们在体内的功能作用,(3)通过蛋白质阵列-表面等离子体共振评估它们与蚊子软骨素糖胺聚糖的结合亲和力。(3)通过分子建模和x射线晶体学,深入了解与软骨素糖胺聚糖片段和结构类似物复合物的分子结构和功能。该项目的第二个目标是开发疟原虫传播阻断糖模拟先导化合物并评估其传播阻断潜力,包括鉴定我们的先导传播阻断化合物VS1(一种非肽基聚乙烯磺化聚合物)的新衍生物和类似物,VS1是中肠软骨素糖胺聚糖的结构模拟物,可抑制蚊子体内95%的寄生虫发育。为了开发更有效的结构类似物,我们提出了一个四层方法:(1)分离不同链长的VS1聚合物,(2)衍生VS1以增强抑制活性和生物利用度,(3)衍生(+)-usnic酸,一种来自地衣的多酚化合物,(4)评估蚊子硫酸软骨素糖胺聚糖的肽模位作为传播阻断疫苗靶点的效用。为了促进临床前研究的进展,我们将分析每种方法的最佳候选化合物在动物和人血清模型中的药代动力学和药效学特性。

项目成果

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Rhoel David Ramos Dinglasan其他文献

Rhoel David Ramos Dinglasan的其他文献

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{{ truncateString('Rhoel David Ramos Dinglasan', 18)}}的其他基金

Relapsing malaria in Africa: mechanisms for persistence amid falciparum decline
非洲疟疾复发:恶性疟下降期间的持续机制
  • 批准号:
    10670794
  • 财政年份:
    2022
  • 资助金额:
    $ 40.18万
  • 项目类别:
CDC Southeastern Center of Excellence in Vector-Borne Diseases: Gateway Program
CDC 东南媒介传播疾病卓越中心:门户计划
  • 批准号:
    10551427
  • 财政年份:
    2022
  • 资助金额:
    $ 40.18万
  • 项目类别:
CDC Southeastern Center of Excellence in Vector-Borne Diseases: Gateway Program
CDC 东南媒介传播疾病卓越中心:门户计划
  • 批准号:
    10655380
  • 财政年份:
    2022
  • 资助金额:
    $ 40.18万
  • 项目类别:
Relapsing malaria in Africa: mechanisms for persistence amid falciparum decline
非洲疟疾复发:恶性疟下降期间的持续机制
  • 批准号:
    10340527
  • 财政年份:
    2022
  • 资助金额:
    $ 40.18万
  • 项目类别:
RFA-GH-21-006, SICA Study: Seroepidemiological Insight into COVID-19 transmission in Africa
RFA-GH-21-006,SICA 研究:非洲 COVID-19 传播的血清流行病学见解
  • 批准号:
    10473447
  • 财政年份:
    2021
  • 资助金额:
    $ 40.18万
  • 项目类别:
SICA Study: Seroepidemiological Insight into COVID-19 transmission in Africa
SICA 研究:非洲 COVID-19 传播的血清流行病学见解
  • 批准号:
    10357031
  • 财政年份:
    2021
  • 资助金额:
    $ 40.18万
  • 项目类别:
RDT-undetectable Malaria in the DR Congo: Epidemiology and Development of Alternatives
刚果民主共和国 RDT 检测不到的疟疾:流行病学和替代方案的开发
  • 批准号:
    10327684
  • 财政年份:
    2018
  • 资助金额:
    $ 40.18万
  • 项目类别:
RDT-undetectable Malaria in the DR Congo: Epidemiology and Development of Alternatives
刚果民主共和国 RDT 检测不到的疟疾:流行病学和替代方案的开发
  • 批准号:
    10475414
  • 财政年份:
    2018
  • 资助金额:
    $ 40.18万
  • 项目类别:
RDT-undetectable Malaria in the DR Congo: Epidemiology and Development of Alternatives
刚果民主共和国 RDT 检测不到的疟疾:流行病学和替代方案的开发
  • 批准号:
    10090556
  • 财政年份:
    2018
  • 资助金额:
    $ 40.18万
  • 项目类别:
RDT-undetectable Malaria in the DR Congo: Epidemiology and Development of Alternatives
刚果民主共和国 RDT 检测不到的疟疾:流行病学和替代方案的开发
  • 批准号:
    10542646
  • 财政年份:
    2018
  • 资助金额:
    $ 40.18万
  • 项目类别:

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