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，一种定义的病原体，也是腹泻病最常见的原因之一 在全球范围内，仍然缺乏任何有效的治疗选择。尽管最近进步，但毒品中的毒品太少 开发管道可确保在高级临床试验中取得成功。由 从明尼苏达州北部的Soudan Iron Ine内部隔离的真菌确定了一组相关的 来自oidiodendron truncatum的北苯后内酯，其中八个具有针对隐孢子虫和的活性 三个针对弓形虫，对哺乳动物宿主细胞没有细胞毒性。发现自然的 可综合的衍生序列，包括具有纳摩尔活性的化合物，针对两个机会主义 病原体允许进行详细的结构活动关系（SAR）研究，可以快速构建 生成一种进入临床前研究的最佳化合物。我们假设这个新发现 抗寄生脚手架将产生具有体内活性和有利的药代动力学参数的化合物 治疗发展。我们进一步假设这些化合物将在 apicomplexans。我们建议以两个具体目的测试这些假设： 目标1：确定衍生物系列的抗寄生功效和药代动力学特性。在这个 目的我们将确定活性化合物的EC50，选择性指数和ADME/PK参数并使用 这些数据选择用于在隐孢子虫感染的严重免疫功能低下的小鼠中进行测试的化合物。 探索性子AIM将识别和测试其他次要结构类似物以扩大结构活动 关系研究。 AIM 2：确定最有效的Oidiodendron衍生物的分子靶标。在这个目标中，我们提出 利用三个衍生物的抗氧化剂活性来进行正向遗传学 实验以识别化合物的靶标。同时，药物亲和力响应靶标稳定性测定 将使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识别。 天然产品具有良好的记录，可作为寄生疾病的有效且强大的治疗疗法；一 需要看起来比青蒿素和ivermectin更远，可以掌握oidiodendron衍生物的潜力 开发新的抗晶状体治疗。某些衍生物的双重活动打开 化合物也可能有效地抵抗与艾滋病相关的弓形虫病有效的可能性。这些 研究是R21机制的理想选择，因为它们具有探索性和高风险/高回报，可能提供 一种新的治疗药效团和一个不可治疗的隐孢子虫病的新治疗靶标。