Target identification and structure optimization of novel thiazole antifungals

新型噻唑类抗真菌药物的靶点鉴定及结构优化

基本信息

  • 批准号:
    8770304
  • 负责人:
  • 金额:
    $ 23.1万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-09-01 至 2016-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Current treatment options for systemic fungal infections remain limited. The development of new antifungals is complicated by the structural and metabolic similarities among fungal and host cells, and the consequent potential for host toxicity. The commonly used polyene and triazole antifungals, which target fungal cell membrane sterols, also affect the stability and production of mammalian cell membrane cholesterol. The recently developed echinocandins are more specific for fungal targets, however they are ineffective in the treatment of Histoplasma capsulatum and Cryptococcus neoformans, leaving the host-toxic polyenes and triazoles as the only methods for treatment of infections caused by these pathogens. From a library of small molecules with structural similarities to purines (e.g., ATP/GTP, NADP, etc.), we identified a series of thiazole-based compounds that have potent antifungal activity against Histoplasma capsulatum and Cryptococcus neoformans. Importantly, these compounds inhibit not only fungal cells in culture but also fungal cells that reside within mammalian host cells following infection. Treatment of Histoplasma-infected macrophages with the thiazole-based antifungals protects host cells from Histoplasma- induced cell death. To mature the top hit antifungal thiazole into a lead candidate for drug development and to better understand its mode of action, this research proposal seeks to identify the cellular target(s) of the antifungal thiazole using affinity and chemical proteomics and to provide initial n vivo efficacy and toxicity studies using an animal model. In addition, derivatives of the thiazole will be prepared and tested to define the structural features necessary for antifungal activity and to improve its chemical properties and maximize antifungal potency.
描述(由申请人提供):目前系统性真菌感染的治疗选择仍然有限。由于真菌和宿主细胞之间的结构和代谢相似性,以及随之而来的宿主毒性,新抗真菌药物的开发变得复杂。常用的多烯类和三唑类抗真菌药,靶向真菌细胞膜固醇,也影响哺乳动物细胞膜胆固醇的稳定性和产生。最近开发的棘白菌素对真菌靶点更具特异性,然而它们在治疗荚膜组织胞浆菌和新型隐球菌中无效,留下宿主毒性多烯和三唑作为治疗由这些病原体引起的感染的唯一方法。从与嘌呤具有结构相似性的小分子文库(例如,ATP/GTP、NADP等),我们鉴定了一系列基于噻唑的化合物,其对荚膜组织胞浆菌和新型隐球菌具有有效的抗真菌活性。重要的是,这些化合物不仅抑制培养物中的真菌细胞,而且抑制感染后驻留在哺乳动物宿主细胞内的真菌细胞。用噻唑类抗真菌剂处理组织胞浆菌感染的巨噬细胞可保护宿主细胞免于组织胞浆菌诱导的细胞死亡。为了将热门抗真菌噻唑成熟为药物开发的主要候选药物,并更好地了解其作用模式,本研究计划旨在使用亲和性和化学蛋白质组学鉴定抗真菌噻唑的细胞靶点,并使用动物模型提供初步的体内疗效和毒性研究。此外,还将制备并测试噻唑衍生物,以确定抗真菌活性所需的结构特征, 以改善其化学性质并最大化抗真菌效力。

项目成果

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Chad A Rappleye其他文献

Chad A Rappleye的其他文献

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{{ truncateString('Chad A Rappleye', 18)}}的其他基金

Intracellular Proliferation of the fungal pathogen Histoplasma capsulatum
真菌病原体荚膜组织胞浆菌的细胞内增殖
  • 批准号:
    10356080
  • 财政年份:
    2020
  • 资助金额:
    $ 23.1万
  • 项目类别:
Intracellular Proliferation of the fungal pathogen Histoplasma capsulatum
真菌病原体荚膜组织胞浆菌的细胞内增殖
  • 批准号:
    10583569
  • 财政年份:
    2020
  • 资助金额:
    $ 23.1万
  • 项目类别:
Forward genetics-based discovery of Histoplasma virulence genes
基于正向遗传学的组织胞浆菌毒力基因发现
  • 批准号:
    8822824
  • 财政年份:
    2014
  • 资助金额:
    $ 23.1万
  • 项目类别:
Forward genetics-based discovery of Histoplasma virulence genes
基于正向遗传学的组织胞浆菌毒力基因发现
  • 批准号:
    8681794
  • 财政年份:
    2014
  • 资助金额:
    $ 23.1万
  • 项目类别:
Virulence factor discovery in the secreted proteome of Histoplasma capsulatum
荚膜组织胞浆菌分泌蛋白质组中毒力因子的发现
  • 批准号:
    8089509
  • 财政年份:
    2009
  • 资助金额:
    $ 23.1万
  • 项目类别:
Virulence factor discovery in the secreted proteome of Histoplasma capsulatum
荚膜组织胞浆菌分泌蛋白质组中毒力因子的发现
  • 批准号:
    8305998
  • 财政年份:
    2009
  • 资助金额:
    $ 23.1万
  • 项目类别:
Virulence factor discovery in the secreted proteome of Histoplasma capsulatum
荚膜组织胞浆菌分泌蛋白质组中毒力因子的发现
  • 批准号:
    7902025
  • 财政年份:
    2009
  • 资助金额:
    $ 23.1万
  • 项目类别:
Virulence factor discovery in the secreted proteome of Histoplasma capsulatum
荚膜组织胞浆菌分泌蛋白质组中毒力因子的发现
  • 批准号:
    7697970
  • 财政年份:
    2009
  • 资助金额:
    $ 23.1万
  • 项目类别:

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