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
• 负责人: ROBERTA M O'CONNOR
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10698574
• 关键词: 2 year old; Acquired Immunodeficiency Syndrome; Adult; Affinity; Antiparasitic Agents; Artemisinins; Bioinformatics; Biological Assay; Biology; Cells; Cessation of life; Child; Chronic; Clinical; Clinical Trials; Complement; Cryptosporidiosis; Cryptosporidium; Data; Developing Countries; Development; Diarrhea; Disease; Disease Outbreaks; Dose; Drug Kinetics; Exhibits; Experimental Genetics; Exploratory/Developmental Grant; Fatigue; Growth; Homologous Gene; Immunocompromised Host; Immunosuppression; Individual; Infection; Iron; Ivermectin; Lactones; Liver Microsomes; Minnesota; Minor; Molecular Target; Mus; Natural Products; Nausea; Norditerpenoids; Oral; Parasites; Parasitic Diseases; Permeability; Persons; Pharmaceutical Preparations; Plasma; Property; Series; Structure-Activity Relationship; Technology; Testing; Therapeutic; Toxoplasma; Toxoplasmosis; analog; cytotoxicity; diarrheal disease; forward genetics; fungus; gastrointestinal; genetic approach; grasp; high risk; immune reconstitution; improved; in vitro testing; in vivo; indexing; marine organism; nanomolar; new therapeutic target; novel therapeutics; opportunistic pathogen; pathogen; pharmacophore; preclinical study; scaffold; screening; success; therapeutic development; therapeutically effective; waterborne; waterborne outbreak

Cryptosporidium, an AIDS-defining pathogen and one of the most common causes of diarrheal disease worldwide, still lacks any effective therapeutic options. Despite recent advances, there are too few drugs in the development pipeline to guarantee success in advanced clinical trials. A screen of compounds produced by fungi isolated from deep within the Soudan Iron Mine in northern Minnesota identified a set of 14 related norditerpene lactones from Oidiodendron truncatum, eight of which have activity against Cryptosporidium and three against Toxoplasma, with no cytotoxicity to mammalian host cells. The discovery of a natural, synthesizable derivative series that includes compounds with nanomolar activity against two opportunistic pathogens allows for a detailed structure activity relationship (SAR) study that can be quickly built upon to generate an optimal compound for entry into preclinical studies. We hypothesize that this newly discovered anti-parasitic scaffold will yield a compound with in vivo activity and pharmacokinetic parameters favorable for therapeutic development. We further hypothesize that these compounds will identify a new druggable target in apicomplexans. We propose to test these hypotheses in two specific aims: Aim 1: Determine anti-parasitic efficacy and pharmacokinetic properties of the derivative series. In this aim we will determine EC50s, selectivity indices and ADME/PK parameters of active compounds and use these data to choose compounds for testing in Cryptosporidium-infected severely immunocompromised mice. An exploratory sub-aim will identify and test additional minor structural analogs to expand the structure activity relationship studies. Aim 2: Identify the molecular target of the most potent Oidiodendron derivatives. In this aim we propose to take advantage of the anti-Toxoplasma activity of three of the derivatives to conduct a forward genetics experiment to identify the target of the compounds. In parallel, drug affinity responsive target stability assays will be conducted with Toxoplasma and Cryptosporidium lysates to complement the data obtained from the genetics approach. Potential homologs in other apicomplexans will be identified by bioinformatics. Natural products have a proven track record as effective and robust therapeutics for parasitic diseases; one need look no farther than artemisinin and ivermectin to grasp the potential of the Oidiodendron derivatives for development of a new anti-Cryptosporidium therapeutic. The dual activity of some of the derivatives opens up the possibility that the compound(s) may also be effective against AIDS-associated toxoplasmosis. These studies are ideal for the R21 mechanism as they are exploratory and high-risk/high return, potentially providing a new therapeutic pharmacophore and a new therapeutic target for untreatable cryptosporidiosis.

隐孢子虫，一种艾滋病定义的病原体，也是腹泻病最常见的原因之一 在世界范围内，仍然缺乏任何有效的治疗选择。尽管最近取得了进展，但市场上的药物仍然太少 开发管道，以保证高级临床试验的成功。筛选产生的化合物 从明尼苏达州北部 Soudan 铁矿深处分离出的真菌鉴定出一组 14 种相关真菌 来自元宝花木的去甲二萜内酯，其中八种具有抗隐孢子虫活性 三种抗弓形虫，对哺乳动物宿主细胞无细胞毒性。自然的发现， 可合成的衍生物系列，包括具有纳摩尔活性的化合物，可对抗两种机会性 病原体允许进行详细的结构活性关系（SAR）研究，可以快速建立在 生成进入临床前研究的最佳化合物。我们假设这个新发现 抗寄生虫支架将产生具有有利于的体内活性和药代动力学参数的化合物 治疗的发展。我们进一步假设这些化合物将识别出新的可成药靶点 顶端复合物。我们建议以两个具体目标来检验这些假设： 目标 1：确定衍生物系列的抗寄生虫功效和药代动力学特性。在这个 目的是确定活性化合物的 EC50、选择性指数和 ADME/PK 参数并使用 这些数据用于选择化合物用于在感染隐孢子虫的严重免疫功能低下的小鼠中进行测试。 探索性子目标将识别和测试额外的次要结构类似物以扩展结构活动 关系研究。 目标 2：确定最有效的 Oidodendron 衍生物的分子靶标。为了这个目标，我们建议 利用其中三种衍生物的抗弓形虫活性进行正向遗传学 实验以确定化合物的目标。同时，药物亲和力响应靶标稳定性测定 将用弓形虫和隐孢子虫裂解物进行，以补充从 遗传学方法。其他apicomplexans中的潜在同源物将通过生物信息学来鉴定。 天然产品作为治疗寄生虫病的有效且强大的疗法已被证明是有效的；一 只需要看看青蒿素和伊维菌素就可以了解 Oidiodendron 衍生物的潜力 开发一种新的抗隐孢子虫疗法。一些衍生品的双重活性开启 该化合物也可能有效对抗艾滋病相关的弓形虫病。这些 研究对于 R21 机制来说是理想的，因为它们是探索性的、高风险/高回报的，有可能提供 无法治疗的隐孢子虫病的新治疗药效基团和新治疗靶点。