Development of a new marine natural product for the treatment of cryptosporidiosis, an AIDS-defining disease

开发一种新的海洋天然产品来治疗隐孢子虫病(一种艾滋病定义的疾病)

基本信息

  • 批准号:
    10631912
  • 负责人:
  • 金额:
    $ 35.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-06-12 至 2025-05-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT There are no effective therapies to treat Cryptosporidium, a waterborne parasite that is now recognized as significant cause of diarrheal disease worldwide and an important AIDS defining pathogen. In the process of mining compounds produced by marine symbiotic bacteria for anti-parasitic activity, we identified a compound, tartrolon E (trtE) that potently inhibits in vitro growth of Cryptosporidium parvum, as well as several other apicomplexan parasites, without toxicity to their respective host cells. We further established that trtE is highly effective at reducing Cryptosporidium infection in neonatal mice. In fact, trtE is 10-fold more effective in vitro and 2-fold more effective in vivo against Cryptosporidium than the most effective compounds reported to date, and the only compound to hold the promise of a broad spectrum anti-apicomplexan therapeutic. These observations strongly encourage further exploration of the clinical potential of trtE for the treatment of cryptosporidiosis. In the studies proposed here, we will test the hypothesis that trtE possesses the activity necessary to be lead candidate therapeutic for the treatment of cryptosporidiosis by completion of the following aims: Aim 1: To evaluate species specificity and life cycle stage specificity of trtE against Cryptosporidium. TrtE will be tested against C. parvum field isolates and C. hominis and the activity of trtE against oocysts, sporozoites, asexual and sexual stages will be determined. Aim 2: To optimize trtE dosing regimens. Pharmacodynamics (A), pharmacokinetics (B) and bioavailability (C) studies will be conducted to design optimal treatment strategies. Aim 3: To evaluate the efficacy of trtE against Cryptosporidium infection in the setting of severe immunosuppression and in a ruminant model of cryptosporidiosis. A. We will test trtE’s ability to inhibit and eliminate Cryptosporidium infection in NOD-SCID gamma mice. B. Because mice do not manifest the symptoms of human disease, we will test the trtE’s ability to inhibit infection and diarrheal illness in neonatal lambs. Aim 4: To optimize production of trtE from Teredinibacter turnerae T7901: Like many natural products, trtE has a complex structure that renders synthesis challenging and prohibitively expensive. The Natural Products Discovery Institute (NPDI), experts in the field of natural product production, will be producing trtE for these studies using established protocols. During that process, NPDI will apply their expertise in this area to increase production efficiency. These studies will provide data essential to establish trtE as a lead candidate for an anti-Cryptosporidium therapeutic. Moreover, because this compound is highly active against multiple parasites, these investigations will underpin future studies evaluating this compound as a broad spectrum therapeutic for diseases caused by apicomplexan parasites, but most critically for cryptosporidiosis, a neglected disease of world-wide significance for which there are no good therapeutic options.
抽象的 目前还没有有效的疗法来治疗隐孢子虫,这是一种现已被认可的水传播寄生虫 是全世界腹泻病的重要原因,也是艾滋病的重要病原体。在此过程中 在海洋共生细菌产生的具有抗寄生虫活性的采矿化合物中,我们发现了一种 化合物 tartrolon E (trtE),可有效抑制小隐孢子虫的体外生长,以及多种 其他顶复门寄生虫,对其各自的宿主细胞没有毒性。我们进一步确定 trtE 是 对减少新生小鼠隐孢子虫感染非常有效。事实上,trtE 的效率提高了 10 倍 体外和体内对抗隐孢子虫的效果比报道的最有效化合物高 2 倍 日期,并且是唯一有望实现广谱抗 apicomplexan 治疗的化合物。这些 观察结果强烈鼓励进一步探索 trtE 治疗以下疾病的临床潜力 隐孢子虫病。在这里提出的研究中,我们将检验 trtE 具有活性的假设 通过完成以下任务,有必要成为治疗隐孢子虫病的主要候选药物 目标: 目标 1:评估 trtE 的物种特异性和生命周期阶段特异性 隐孢子虫。 TrtE 将针对 C. parvum 田间分离株和 C. hominis 进行测试以及 trtE 的活性 针对卵囊、子孢子、无性和有性阶段将被确定。目标 2:优化 trtE 剂量 治疗方案。将进行药效学(A)、药代动力学(B)和生物利用度(C)研究 设计最佳治疗策略。目标 3:评估 trtE 对隐孢子虫的功效 严重免疫抑制环境和隐孢子虫病反刍动物模型中的感染。一个。 我们将在 NOD-SCID γ 小鼠中测试 trtE 抑制和消除隐孢子虫感染的能力。 B. 由于小鼠不会表现出人类疾病的症状,因此我们将测试trtE抑制感染的能力 和新生羔羊的腹泻病。目标 4:优化 Teredinibacter 的 trtE 生产 Turnerae T7901:与许多天然产物一样,trtE 具有复杂的结构,使得合成具有挑战性 而且价格昂贵得令人望而却步。天然产物发现研究所(NPDI),天然领域的专家 产品生产,将使用既定方案生产用于这些研究的 trtE。在此过程中, NPDI 将运用他们在该领域的专业知识来提高生产效率。这些研究将提供数据 对于将 trtE 确立为抗隐孢子虫治疗的主要候选药物至关重要。而且,因为这 该化合物对多种寄生虫具有高度活性,这些研究将为未来的研究奠定基础 评估该化合物作为治疗由顶复门寄生虫引起的疾病的广谱治疗剂, 但最关键的是隐孢子虫病,这是一种具有世界范围重要性的被忽视的疾病,目前还没有针对它的治疗方法。 良好的治疗选择。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The Marine Compound Tartrolon E Targets the Asexual and Early Sexual Stages of Cryptosporidium parvum.
海洋化合物塔罗龙E靶向隐孢子虫的无性和早期性阶段。
  • DOI:
    10.3390/microorganisms10112260
  • 发表时间:
    2022-11-15
  • 期刊:
  • 影响因子:
    4.5
  • 作者:
  • 通讯作者:
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

ROBERTA M O'CONNOR其他文献

ROBERTA M O'CONNOR的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('ROBERTA M O'CONNOR', 18)}}的其他基金

Antiparasitic metabolites from deep subterranean fungi for the treatment of cryptosporidiosis, an AIDS defining disease
来自深层地下真菌的抗寄生虫代谢物用于治疗隐孢子虫病(一种艾滋病定义的疾病)
  • 批准号:
    10698574
  • 财政年份:
    2023
  • 资助金额:
    $ 35.13万
  • 项目类别:
Development of a new marine natural product for the treatment of cryptosporidiosis, an AIDS-defining disease
开发一种新的海洋天然产品来治疗隐孢子虫病(一种艾滋病定义的疾病)
  • 批准号:
    10495750
  • 财政年份:
    2020
  • 资助金额:
    $ 35.13万
  • 项目类别:
Development of a new marine natural product for the treatment of cryptosporidiosis, an AIDS-defining disease
开发一种新的海洋天然产品来治疗隐孢子虫病(一种艾滋病定义的疾病)
  • 批准号:
    10402287
  • 财政年份:
    2020
  • 资助金额:
    $ 35.13万
  • 项目类别:
Development of a new marine natural product for the treatment of cryptosporidiosis, an AIDS-defining disease
开发一种新的海洋天然产品来治疗隐孢子虫病(一种艾滋病定义的疾病)
  • 批准号:
    10076207
  • 财政年份:
    2020
  • 资助金额:
    $ 35.13万
  • 项目类别:
Investigation of a shipworm endosymbiont compound with activity against the AIDS-associated pathogens Cryptosporidium and Toxoplasma
对具有抗艾滋病相关病原体隐孢子虫和弓形虫活性的船虫内共生化合物的研究
  • 批准号:
    9267939
  • 财政年份:
    2017
  • 资助金额:
    $ 35.13万
  • 项目类别:
Investigation of a shipworm endosymbiont compound with activity against the AIDS-associated pathogens Cryptosporidium and Toxoplasma
对具有抗艾滋病相关病原体隐孢子虫和弓形虫活性的船虫内共生化合物的研究
  • 批准号:
    9431036
  • 财政年份:
    2017
  • 资助金额:
    $ 35.13万
  • 项目类别:
T. gondii as a model for investigation of Cryptosporidium glycoprotein antigens
弓形虫作为研究隐孢子虫糖蛋白抗原的模型
  • 批准号:
    8111486
  • 财政年份:
    2010
  • 资助金额:
    $ 35.13万
  • 项目类别:
T. gondii as a model for investigation of Cryptosporidium glycoprotein antigens
弓形虫作为研究隐孢子虫糖蛋白抗原的模型
  • 批准号:
    7756965
  • 财政年份:
    2009
  • 资助金额:
    $ 35.13万
  • 项目类别:
T. gondii as a model for investigation of Cryptosporidium glycoprotein antigens
弓形虫作为研究隐孢子虫糖蛋白抗原的模型
  • 批准号:
    7893819
  • 财政年份:
    2009
  • 资助金额:
    $ 35.13万
  • 项目类别:
Role of Cryptosporidium Mucins in Host-parasite interactions
隐孢子虫粘蛋白在宿主-寄生虫相互作用中的作用
  • 批准号:
    7168031
  • 财政年份:
    2006
  • 资助金额:
    $ 35.13万
  • 项目类别:

相似海外基金

Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
  • 批准号:
    MR/Y009568/1
  • 财政年份:
    2024
  • 资助金额:
    $ 35.13万
  • 项目类别:
    Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
  • 批准号:
    10090332
  • 财政年份:
    2024
  • 资助金额:
    $ 35.13万
  • 项目类别:
    Collaborative R&D
Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
  • 批准号:
    MR/X02329X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 35.13万
  • 项目类别:
    Fellowship
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
  • 批准号:
    MR/X021882/1
  • 财政年份:
    2024
  • 资助金额:
    $ 35.13万
  • 项目类别:
    Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
  • 批准号:
    2312694
  • 财政年份:
    2024
  • 资助金额:
    $ 35.13万
  • 项目类别:
    Standard Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
  • 批准号:
    EP/Y003527/1
  • 财政年份:
    2024
  • 资助金额:
    $ 35.13万
  • 项目类别:
    Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
  • 批准号:
    EP/Y030338/1
  • 财政年份:
    2024
  • 资助金额:
    $ 35.13万
  • 项目类别:
    Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
  • 批准号:
    MR/X029557/1
  • 财政年份:
    2024
  • 资助金额:
    $ 35.13万
  • 项目类别:
    Research Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
  • 批准号:
    24K19395
  • 财政年份:
    2024
  • 资助金额:
    $ 35.13万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Acute human gingivitis systems biology
人类急性牙龈炎系统生物学
  • 批准号:
    484000
  • 财政年份:
    2023
  • 资助金额:
    $ 35.13万
  • 项目类别:
    Operating Grants
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了