Drug Target Discovery, Validation, and Prioritization for Schistosomiasis

血吸虫病药物靶标的发现、验证和优先排序

基本信息

  • 批准号:
    10584296
  • 负责人:
  • 金额:
    $ 81.93万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-12-20 至 2027-11-30
  • 项目状态:
    未结题

项目摘要

Schistosomes infect 200 million of the world’s poorest people. Although these parasites kill 250,000 people annually, and rob millions more the ability to lead healthy and productive lives, treatment of schistosome infection relies on a single drug (Praziquantel). Unfortunately, Praziquantel is not a magic bullet. Indeed, praziquantel is not equally effective against all intramammalian stages of the parasite’s life cycle and it suffers from a variable cure rate in some endemic settings. This later point, raises the specter that praziquantel-resistant parasites could emerge as organizations ramp up mass drug administration programs. Indeed, several studies have demonstrated that strains with reduced sensitivity to praziquantel can be rapidly selected in the laboratory. Therefore, efforts to develop the next generation of antischistosome therapies to replace praziquantel are key to a sustained effort to eradicate this disease. Drug development efforts against schistosomes suffer from two important limitations. First, the large size of the adult parasites (~1cm in length) makes screening thousands of compounds for activity against the worm impractical. The second important limitation is that we only know the function of a small number of proteins in these worms making it challenging conduct informed target-based drug discovery efforts. To address these issues, we have conducted the first large-scale loss-of-function RNA interference (RNAi) screen in adult schistosomes. Using this platform, we have performed over 2000 individual RNAi knockdown experiments in adult Schistosoma mansoni and identified nearly two hundred genes, a large fraction of which are potentially druggable, that are essential for parasite survival and/or neuromuscular function both in vitro and in vivo inside mice. To capitalize on these studies we will execute three specific aims to discover and experimentally prioritize druggable targets in the schistosome. In Specific Aim 1, we will utilize RNAi and in silico approaches to identify and prioritize druggable targets that are essential in vitro and in vivo in three medically relevant schistosome species. In Specific Aim 2, we will experimentally validate the druggability of the highest priority targets from Aim 1 by assessing the performance of these targets in small-scale high throughput small molecule screens. These studies will identify both validated druggable targets in the schistosome that can form the basis of future drug discovery campaigns and compounds poised for lead optimization efforts.
血吸虫感染了世界上2亿最贫穷的人。尽管这些寄生虫杀死 每年25万人,并剥夺数百万人健康和高效领导的能力 尽管如此,血吸虫感染的治疗依赖于一种药物(吡喹酮)。不幸的是, 吡喹酮不是灵丹妙药。事实上,吡喹酮并不是对所有人都同样有效 在哺乳动物内寄生虫生命周期的各个阶段,它的治愈率在 一些地方性的环境。这之后的一点,引发了对吡喹酮耐药的幽灵 随着组织加大大规模药物管理项目的力度,寄生虫可能会出现。 事实上,几项研究已经证明,对药物敏感性降低的菌株 在实验室中可以快速选择吡喹酮。因此,努力发展下一步 替代吡喹酮的新一代抗血吸虫疗法是持续努力的关键 来根除这种疾病。针对血吸虫的药物开发工作受到两个方面的影响 重要的局限性。首先,成虫的大尺寸(~1厘米长)使 筛选数以千计的化合物对蠕虫的活性不切实际。第二 重要的限制是,我们只知道其中一小部分蛋白质的功能。 蠕虫使其具有挑战性,进行基于知情的靶向药物发现努力。至 针对这些问题,我们进行了第一次大规模的功能丧失RNA 在成虫中进行干扰(RNAi)筛选。利用这个平台,我们已经完成了 在曼氏血吸虫成虫和成虫体内进行了2000多个RNAi敲除实验 确定了近200个基因,其中很大一部分可能是可下药的, 在体外和体内对寄生虫的存活和/或神经肌肉功能都是必不可少的 在老鼠体内。为了利用这些研究,我们将执行三个具体目标来发现 并在实验中优先考虑血吸虫中的可用药靶点。在具体目标1中,我们将 利用RNAi和电子计算机方法来识别和优先处理下列可用药靶点 在三种医学上相关的血吸虫物种体内和体外都是必需的。以特定的目标 2,我们将通过实验验证来自目标1的最高优先级目标的可药性 这些靶在小规模高通量小分子中的性能评估 屏幕。这些研究将确定血吸虫中两个有效的可用药靶点 可以构成未来药物发现活动和化合物的基础 优化努力。

项目成果

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James J Collins其他文献

Comparative Analysis of Cas9 Activators Across Multiple Species
多个物种 Cas9 激活剂的比较分析
  • DOI:
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Alejandro Chavez;Marcelle Tuttle;Benjamin W Pruitt;Ben Ewen;Raj;Chari;Dmitry Ter;Sabina J. Haque;Ryan J. Cecchi;Emma J K Kowal;Joanna Buchthal;B. Housden;N. Perrimon;James J Collins;George Church
  • 通讯作者:
    George Church
Insulating gene circuits from context by RNA processing
通过 RNA 加工使基因回路与环境绝缘
  • DOI:
    10.1038/nbt.2411
  • 发表时间:
    2012-11-08
  • 期刊:
  • 影响因子:
    41.700
  • 作者:
    Caleb J Bashor;James J Collins
  • 通讯作者:
    James J Collins
RNA synthetic biology
RNA 合成生物学
  • DOI:
    10.1038/nbt1208
  • 发表时间:
    2006-05-05
  • 期刊:
  • 影响因子:
    41.700
  • 作者:
    Farren J Isaacs;Daniel J Dwyer;James J Collins
  • 通讯作者:
    James J Collins
Machine learning for synthetic gene circuit engineering
用于合成基因电路工程的机器学习
  • DOI:
    10.1016/j.copbio.2025.103263
  • 发表时间:
    2025-04-01
  • 期刊:
  • 影响因子:
    7.000
  • 作者:
    Sebastian Palacios;James J Collins;Domitilla Del Vecchio
  • 通讯作者:
    Domitilla Del Vecchio

James J Collins的其他文献

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{{ truncateString('James J Collins', 18)}}的其他基金

Characterizing sexual development of the human parasite Schistosoma mansoni
人类寄生虫曼氏血吸虫的性发育特征
  • 批准号:
    10207379
  • 财政年份:
    2020
  • 资助金额:
    $ 81.93万
  • 项目类别:
Characterizing sexual development of the human parasite Schistosoma mansoni
人类寄生虫曼氏血吸虫的性发育特征
  • 批准号:
    10441417
  • 财政年份:
    2020
  • 资助金额:
    $ 81.93万
  • 项目类别:
Characterizing sexual development of the human parasite Schistosoma mansoni
人类寄生虫曼氏血吸虫的性发育特征
  • 批准号:
    10652328
  • 财政年份:
    2020
  • 资助金额:
    $ 81.93万
  • 项目类别:
The Biology of Stem Cells in the Human Parasite Schistosoma Mansoni
人类寄生虫曼氏血吸虫干细胞的生物学
  • 批准号:
    9207424
  • 财政年份:
    2016
  • 资助金额:
    $ 81.93万
  • 项目类别:
The Biology of Stem Cells in the Human Parasite Schistosoma Mansoni
人类寄生虫曼氏血吸虫干细胞的生物学
  • 批准号:
    10210085
  • 财政年份:
    2016
  • 资助金额:
    $ 81.93万
  • 项目类别:
The Biology of Stem Cells in the Human Parasite Schistosoma Mansoni
人类寄生虫曼氏血吸虫干细胞的生物学
  • 批准号:
    10544522
  • 财政年份:
    2016
  • 资助金额:
    $ 81.93万
  • 项目类别:
The Biology of Stem Cells in the Human Parasite Schistosoma Mansoni
人类寄生虫曼氏血吸虫干细胞的生物学
  • 批准号:
    9121333
  • 财政年份:
    2016
  • 资助金额:
    $ 81.93万
  • 项目类别:
The characterization of neuropeptides in the Planarian Schmidtea mediterranea
地中海涡虫中神经肽的表征
  • 批准号:
    7982539
  • 财政年份:
    2009
  • 资助金额:
    $ 81.93万
  • 项目类别:
The characterization of neuropeptides in the Planarian Schmidtea mediterranea
地中海涡虫中神经肽的表征
  • 批准号:
    7750680
  • 财政年份:
    2009
  • 资助金额:
    $ 81.93万
  • 项目类别:

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