Occidiofungin as a new lead against the enteric AIDS-OI cryptosporidium

Occidiofungin 是对抗肠道 AIDS-OI 隐孢子虫的新药物

基本信息

  • 批准号:
    10380785
  • 负责人:
  • 金额:
    $ 18.56万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-04-01 至 2024-03-31
  • 项目状态:
    已结题

项目摘要

Project Summary The enteric protozoan Cryptosporidium is an AIDS-OI pathogen, a water-borne parasite that caused >100 deaths in the 1993 outbreak in Milwaukee, WI. Cryptosporidium is a biodefense category B agent, presenting a credible security threat. It is also one of the top few diarrheal agents that afflicts children in developing countries. However, no drugs are FDA-approved to treat cryptosporidiosis in AIDS patients. Nitazoxanide is the only drug approved for use in immune-competent individuals, whereas it is not fully effective. Therefore, there is a need to develop new anti-cryptosporidium drugs, particularly for AIDS patients and children. This project is developed based on recent observation that occidiofungin, a glycolipopeptide, possessed outstanding anti-cryptosporidium activity in vitro with limited cytotoxicity (EC50 = 120−138 nM vs. TC50 = ~1.0−2.5 μM). Occidiofungin is an amphipathic molecule, consisting of a hydrophilic body and a hydrophobic tail. It is nonabsorbable by the digestive system, and could be accumulated in the gastrointestinal tract. Because Cryptosporidium differs from other apicomplexans by its unique “epi-cytoplasmic” lifestyle (i.e., intracellular, but extra-cytoplasmic on the intestinal epithelia), a non-systemic drug with mucoadhesive property like occidiofungin has the advantage to act more effectively on the parasite. The strong preliminary data allows the team to build a central hypothesis that the non-systemic occidiofungin can serve as a novel structure for potentially developing new anti-cryptosporidium therapeutics. To test the hypothesis, the team will conduct in vivo experiments to achieve the following two specific aims: Aim 1 is to definitively verify the anti-cryptosporidium activity of occidiofungin two mouse models: an acute infection model in IL-12 knockout mice, and a newly developed chronic infection model in R2G2 mice. Aim 2 is to determine the gastrointestinal pharmacokinetics of occidiofungin, including its distributing kinetics in the luminal contents, mucus layers and mucosa among various GI segments, and its correlation with anti- cryptosporidium efficacy. Its mucoadhesive property in vitro will also be investigated. The long-term goal of the project is to explore non-systemic drugs for potential development of therapeutics against the enteric cryptosporidium. The completion of the two aims will ultimately determine whether occidiofungin can be pursued further as an anti-cryptosporidium lead, and justify next stage of investigation (e.g., lead optimization and formulation aimed to improve the mucoadhesive property, anti-parasitic efficacy, selectivity and safety). Data obtained in this project may also provide basis for exploring the potential of occidiofungin and its derivatives against other enteric parasites (such as Giardia and Entamoeba).
项目摘要 肠道原生动物隐孢子虫是一种AIDS-OI病原体,一种水传播的寄生虫, 1993年威斯康星州密尔沃基爆发的死亡人数。隐孢子虫是一种生物防御B类病原体, 一个可信的安全威胁它也是少数几种影响儿童发育的重要病原体之一。 国家然而,没有药物被FDA批准用于治疗艾滋病患者的隐孢子虫病。硝唑尼特是 是唯一一种被批准用于有免疫能力的个体的药物,但它并不完全有效。因此,我们认为, 需要开发新的抗隐孢子虫药物,特别是用于AIDS患者和儿童。 本项目是基于最近的观察,occidiofungin,一种糖脂肽, 在体外具有显著的抗隐孢子虫活性,细胞毒性有限(EC 50 = 120 - 138 nM,TC 50 = 120 - 138 nM)。 ~1.0−2.5 μM)。Occidiofungin是一种两亲分子,由亲水体和疏水体组成。 尾巴它不能被消化系统吸收,并可能在胃肠道中蓄积。 由于隐孢子虫与其他顶复门的不同之处在于其独特的“外细胞质”生活方式(即, 细胞内,但在肠上皮细胞上的细胞质外),一种具有粘膜粘附性的非全身性药物 类似于球孢子菌素的特性具有更有效地作用于寄生虫的优点。 强有力的初步数据使研究小组能够建立一个中心假设,即非系统性的occidiofungin 可作为潜在开发新的抗隐孢子虫治疗剂的新结构。测试 假设,该团队将进行体内实验,以实现以下两个具体目标: 目的1是明确验证球孢子菌素的抗隐孢子虫活性的两种小鼠模型:急性 在IL-12敲除小鼠中的感染模型和在R2 G2小鼠中的新开发的慢性感染模型。 目的2:研究西地芬净的胃肠道药动学,包括其分布动力学 胃肠道各节段间肠内容物、粘液层和粘膜中抗- 隐孢子虫功效还将研究其体外粘膜粘附特性。 该项目的长期目标是探索非全身性药物,用于潜在的治疗学开发 对抗肠道隐孢子虫这两个目标的完成将最终决定 球孢子菌素可以作为抗隐孢子虫的先导药物进一步研究,并证明下一阶段的研究是合理的 (e.g.,先导优化和配方旨在改善粘膜粘附性能,抗寄生虫功效, 选择性和安全性)。本项目获得的数据也可为探索 抗其他肠道寄生虫(如贾第虫和内阿米巴)的球孢子菌素及其衍生物。

项目成果

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Ramesh Vemulapalli其他文献

Ramesh Vemulapalli的其他文献

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{{ truncateString('Ramesh Vemulapalli', 18)}}的其他基金

Occidiofungin as a new lead against the enteric AIDS-OI cryptosporidium
Occidiofungin 是对抗肠道 AIDS-OI 隐孢子虫的新药物
  • 批准号:
    10254631
  • 财政年份:
    2021
  • 资助金额:
    $ 18.56万
  • 项目类别:
Brucellosis Research Conference 2009
2009 年布鲁氏菌病研究会议
  • 批准号:
    7750419
  • 财政年份:
    2009
  • 资助金额:
    $ 18.56万
  • 项目类别:
Non-replicative Vaccine for Human Brucellosis
人类布鲁氏菌病非复制疫苗
  • 批准号:
    7372590
  • 财政年份:
    2007
  • 资助金额:
    $ 18.56万
  • 项目类别:
Non-replicative Vaccine for Human Brucellosis
人类布鲁氏菌病非复制疫苗
  • 批准号:
    7737879
  • 财政年份:
    2007
  • 资助金额:
    $ 18.56万
  • 项目类别:
Non-replicative Vaccine for Human Brucellosis
人类布鲁氏菌病非复制疫苗
  • 批准号:
    7537178
  • 财政年份:
    2007
  • 资助金额:
    $ 18.56万
  • 项目类别:
Non-replicative Vaccine for Human Brucellosis
人类布鲁氏菌病非复制疫苗
  • 批准号:
    7995977
  • 财政年份:
    2007
  • 资助金额:
    $ 18.56万
  • 项目类别:
B.abortus-based vaccine against viral hemorrhagic fevers
基于流产双歧杆菌的病毒性出血热疫苗
  • 批准号:
    6773347
  • 财政年份:
    2003
  • 资助金额:
    $ 18.56万
  • 项目类别:
B.abortus-based vaccine against viral hemorrhagic fevers
基于流产双歧杆菌的病毒性出血热疫苗
  • 批准号:
    6682230
  • 财政年份:
    2003
  • 资助金额:
    $ 18.56万
  • 项目类别:

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