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：
Ramesh Vemulapalli
金额：
$ 18.56万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
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

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

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).

项目概要肠道原生动物隐孢子虫是一种 AIDS-OI 病原体，是一种水传播寄生虫，导致 >100 1993 年威斯康星州密尔沃基爆发的隐孢子虫是一种生物防御 B 类病原体，导致死亡。它也是一种严重影响发育中儿童的腹泻病原。然而，FDA 还没有批准用于治疗艾滋病患者隐孢子虫病的药物。唯一被批准用于免疫能力强的个体的药物，但它并不完全有效。需要开发新的抗隐孢子虫药物，特别是针对艾滋病患者和儿童。该项目是根据最近的观察而开发的，occidiofungin（一种糖脂肽）具有体外具有出色的抗隐孢子虫活性，且细胞毒性有限（EC50 = 120−138 nM vs. TC50 = ~1.0−2.5 μM）。 Occidiofungin 是一种两亲性分子，由亲水体和疏水体组成。尾部不被消化系统吸收，可在胃肠道中蓄积。因为隐孢子虫因其独特的“表胞质”生活方式（即，细胞内，但肠上皮细胞质外），一种具有粘膜粘附性的非全身性药物像occidiofungin这样的特性具有对寄生虫更有效的作用的优势。强有力的初步数据使团队能够建立一个中心假设，即非系统性occidiofungin 可以作为潜在开发新的抗隐孢子虫疗法的新结构来测试。假设，团队将进行体内实验以实现以下两个具体目标：目标 1 是明确验证 occidiofungin 两种小鼠模型的抗隐孢子虫活性：急性 IL-12敲除小鼠感染模型，以及新开发的R2G2小鼠慢性感染模型。目标 2 是确定 occidiofungin 的胃肠道药代动力学，包括其分布动力学不同胃肠道节段的管腔内容物、粘液层和粘膜的变化及其与抗- 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系统性药物以开发潜在的治疗方法对抗肠道隐孢子虫的完成将最终决定这两个目标的实现。 occidiofungin 可以作为抗隐孢子虫先导药物进一步研究，并证明下一阶段的研究是合理的（例如，旨在提高粘膜粘附特性、抗寄生虫功效的先导化合物优化和配方，该项目获得的数据也可为探索潜力提供基础 occidiofungin 及其衍生物对抗其他肠道寄生虫（如贾第鞭毛虫和内阿米巴）。