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: 10380785
• 负责人: Ramesh Vemulapalli
• 金额: $ 18.56万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10380785
• 关键词: Abbreviations; Acquired Immunodeficiency Syndrome; Adhesives; Antifungal Agents; Antiparasitic Agents; Biochemistry; Categories; Cells; Cessation of life; Child; Cryptosporidiosis; Cryptosporidium; Cryptosporidium parvum; Data; Developing Countries; Development; Diarrhea; Disease Outbreaks; Drug Formulations; Drug Kinetics; Electrons; Entamoeba; Enteral; FDA approved; Formulation; Gastrointestinal tract structure; Giardia; Goals; Hour; Hydrophobicity; Immunocompetent; Immunocompromised Host; Immunofluorescence Microscopy; In Vitro; Individual; Infection; Interleukin-12; Investigation; Kinetics; Knockout Mice; Lead; Life; Life Style; Membrane; Modeling; Mucous Membrane; Mucous body substance; Mus; Opportunistic Infections; Parasites; Parasitology; Patients; Permeability; Pharmaceutical Preparations; Pharmacology Study; Property; Safety; Security; Structure; Tail; Testing; Therapeutic; Vacuole; acute infection; antimicrobial; base; beta-Cyclodextrins; biodefense; chronic infection; cytotoxic; cytotoxicity; drug discovery; experimental study; gastrointestinal; gastrointestinal system; glycolipopeptide; hydrophilicity; improved; in vitro activity; in vivo; intestinal epithelium; kinase inhibitor; lead optimization; mouse model; nanomolar; nitazoxanide; novel; novel therapeutics; pathogen; preclinical study; therapeutic development; virtual; waterborne; Abbreviations; Acquired Immunodeficiency Syndrome; Adhesives; Antifungal Agents; Antiparasitic Agents; Biochemistry; Categories; Cells; Cessation of life; Child; Cryptosporidiosis; Cryptosporidium; Cryptosporidium parvum; Data; Developing Countries; Development; Diarrhea; Disease Outbreaks; Drug Formulations; Drug Kinetics; Electrons; Entamoeba; Enteral; FDA approved; Formulation; Gastrointestinal tract structure; Giardia; Goals; Hour; Hydrophobicity; Immunocompetent; Immunocompromised Host; Immunofluorescence Microscopy; In Vitro; Individual; Infection; Interleukin-12; Investigation; Kinetics; Knockout Mice; Lead; Life; Life Style; Membrane; Modeling; Mucous Membrane; Mucous body substance; Mus; Opportunistic Infections; Parasites; Parasitology; Patients; Permeability; Pharmaceutical Preparations; Pharmacology Study; Property; Safety; Security; Structure; Tail; Testing; Therapeutic; Vacuole; acute infection; antimicrobial; base; beta-Cyclodextrins; biodefense; chronic infection; cytotoxic; cytotoxicity; drug discovery; experimental study; gastrointestinal; gastrointestinal system; glycolipopeptide; hydrophilicity; improved; in vitro activity; in vivo; intestinal epithelium; kinase inhibitor; lead optimization; mouse model; nanomolar; nitazoxanide; novel; novel therapeutics; pathogen; preclinical study; therapeutic development; virtual; waterborne

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，它是一种造成100> 100的水传播寄生虫 1993年在威斯康星州密尔沃基的爆发中死亡。隐孢子虫是Biodefense B类代理，呈现 可靠的安全威胁。它也是困扰儿童发展的前几个腹泻剂之一 国家。但是，没有药物批准为治疗艾滋病患者的隐孢子虫病。奈塔唑尼德是 唯一被批准用于免疫能力的人的药物，而该药物尚未完全有效。所以， 有必要开发新的抗氯孢子虫药物，尤其是针对艾滋病患者和儿童。 该项目是根据最近的观察结果开发的 在体外具有有限的细胞毒性（EC50 = 120-138 nm与TC50 = 〜1.0-2.5μm）。 Occidiofungin是一种两亲分子，由亲水体和疏水组成 尾巴。消化系统不可吸收，并且可以累积在胃肠道中。 因为隐孢子虫通过其独特的“ Epi-Cytoplasmic”生活方式与其他Apicomplexans不同（即， 细胞内但外胞质外皮细胞质），一种非系统性药物，具有粘附性 诸如Occidiofungin之类的财产具有更有效地对寄生虫作用的优势。 强大的初步数据允许团队建立一个核心假设，即非系统性的Occidiofungin 可以用作一种新型结构，用于可能开发新的抗晶状体孢子虫治疗。测试 假设，团队将进行体内实验，以实现以下两个具体目标： AIM 1是确定验证occidiofungin的抗晶状体孢子活性两种小鼠模型：急性 IL-12敲除小鼠中的感染模型，以及在R2G2小鼠中新开发的慢性感染模型。 AIM 2是确定Occidiofungin的胃肠道药代动力学，包括其分布动力学 在腔内含量中，粘液层和粘膜在各个胃肠道段之间，及其与抗 - 的相关性 隐孢子虫效率。它在体外的粘粘性特性也将进行研究。 该项目的长期目标是探索非系统性药物以进行治疗的潜在发展 针对启动子隐孢子虫。两个目标的完成最终将确定是否是否 可以作为抗晶状体的铅进一步追求Occidiofungin，并证明下一阶段的调查是合理的 （例如，铅优化和公式旨在提高粘附性能，抗寄生态效率， 选择性和安全性）。该项目中获得的数据也可能为探索潜力提供基础 Occidiofungin及其针对其他肠道寄生虫（例如贾第鞭毛虫和Entamoeba）的衍生物。