Development of a new marine natural product for the treatment of cryptosporidiosis, an AIDS-defining disease

开发一种新的海洋天然产品来治疗隐孢子虫病（一种艾滋病定义的疾病）

基本信息

批准号：
10076207
负责人：
ROBERTA M O'CONNOR
金额：
$ 47.41万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-12 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10076207
关键词：
Acquired Immunodeficiency Syndrome Acute Antiparasitic Agents Area Bacteria Biological Availability Cells Cessation of life Characteristics Chronic Clinical Complex Consumption Cryptosporidiosis Cryptosporidium Cryptosporidium parvum Data Developed Countries Developing Countries Development Diarrhea Disease Dose Drug Kinetics Future Growth Immune Immunocompromised Host Immunosuppression In Vitro Individual Infant Infection Institutes Intestines Invertebrates Investigation Length Life Cycle Stages Luciferases Medical Mining Modeling Mus Natural Products Neonatal Oocysts Organoids Parasites Patients Pharmaceutical Preparations Pharmacodynamics Process Production Property Protocols documentation Regimen Reporting Ruminants Species Specificity Specificity Sporozoites Staphylococcus hominis Structure Symptoms Testing Therapeutic Time Toxic effect Treatment Efficacy Wood material Work asexual design diarrheal disease effective therapy gastrointestinal human disease immunosuppressed in vivo innovation lead candidate marine natural product mouse model neglect nitazoxanide optimal treatments pathogen symbiont therapeutic candidate treatment optimization treatment strategy waterborne waterborne outbreak

项目摘要

ABSTRACT There are no effective therapies to treat Cryptosporidium, a waterborne parasite that is now recognized as significant cause of diarrheal disease worldwide and an important AIDS defining pathogen. In the process of mining compounds produced by marine symbiotic bacteria for anti-parasitic activity, we identified a compound, tartrolon E (trtE) that potently inhibits in vitro growth of Cryptosporidium parvum, as well as several other apicomplexan parasites, without toxicity to their respective host cells. We further established that trtE is highly effective at reducing Cryptosporidium infection in neonatal mice. In fact, trtE is 10-fold more effective in vitro and 2-fold more effective in vivo against Cryptosporidium than the most effective compounds reported to date, and the only compound to hold the promise of a broad spectrum anti-apicomplexan therapeutic. These observations strongly encourage further exploration of the clinical potential of trtE for the treatment of cryptosporidiosis. In the studies proposed here, we will test the hypothesis that trtE possesses the activity necessary to be lead candidate therapeutic for the treatment of cryptosporidiosis by completion of the following aims: Aim 1: To evaluate species specificity and life cycle stage specificity of trtE against Cryptosporidium. TrtE will be tested against C. parvum field isolates and C. hominis and the activity of trtE against oocysts, sporozoites, asexual and sexual stages will be determined. Aim 2: To optimize trtE dosing regimens. Pharmacodynamics (A), pharmacokinetics (B) and bioavailability (C) studies will be conducted to design optimal treatment strategies. Aim 3: To evaluate the efficacy of trtE against Cryptosporidium infection in the setting of severe immunosuppression and in a ruminant model of cryptosporidiosis. A. We will test trtE’s ability to inhibit and eliminate Cryptosporidium infection in NOD-SCID gamma mice. B. Because mice do not manifest the symptoms of human disease, we will test the trtE’s ability to inhibit infection and diarrheal illness in neonatal lambs. Aim 4: To optimize production of trtE from Teredinibacter turnerae T7901: Like many natural products, trtE has a complex structure that renders synthesis challenging and prohibitively expensive. The Natural Products Discovery Institute (NPDI), experts in the field of natural product production, will be producing trtE for these studies using established protocols. During that process, NPDI will apply their expertise in this area to increase production efficiency. These studies will provide data essential to establish trtE as a lead candidate for an anti-Cryptosporidium therapeutic. Moreover, because this compound is highly active against multiple parasites, these investigations will underpin future studies evaluating this compound as a broad spectrum therapeutic for diseases caused by apicomplexan parasites, but most critically for cryptosporidiosis, a neglected disease of world-wide significance for which there are no good therapeutic options.

抽象的目前还没有有效的疗法来治疗隐孢子虫，这是一种现已被认可的水传播寄生虫是全世界腹泻病的重要原因，也是艾滋病的重要病原体。在海洋共生细菌产生的具有抗寄生虫活性的采矿化合物中，我们发现了一种化合物 tartrolon E (trtE)，可有效抑制小隐孢子虫的体外生长，以及多种其他 apicomplexan 寄生虫，对其各自的宿主细胞没有毒性我们进一步确定 trtE 是。在减少新生小鼠的隐孢子虫感染方面非常有效。事实上，trtE 对减少隐孢子虫感染的效果要高出 10 倍。与报道的最有效化合物相比，体外和体内对抗隐孢子虫的效果高出 2 倍日期，并且是唯一有望实现广谱抗 apicomplexan 治疗的化合物。观察结果强烈鼓励进一步探索 trtE 治疗的临床潜力在此提出的研究中，我们将检验 trtE 具有该活性的假设。通过完成以下任务，有必要成为治疗隐孢子虫病的主要候选药物目标：目标 1：评估 trtE 的物种特异性和生命周期阶段特异性将对隐孢子虫 (Cryptosporidium) 进行针对小隐孢子虫 (C. parvum) 现场分离株和人隐孢子虫 (C. hominis) 的测试以及 trtE 的活性。将确定针对卵囊、子孢子、无性和有性阶段的目标 2：优化 trtE 剂量。将进行药效学（A）、药代动力学（B）和生物利用度（C）研究。设计最佳治疗策略：评估 trtE 对隐孢子虫的功效。严重免疫抑制情况下和隐孢子虫病反刍动物模型中的感染。我们将测试 trtE 在 NOD-SCID γ 小鼠中抑制和消除隐孢子虫感染的能力。由于小鼠不会表现出人类疾病的症状，因此我们将测试trtE抑制感染的能力目标 4：优化 Teredinibacter 的 trtE 生产。 Turnerae T7901：与许多天然产物一样，trtE 具有复杂的结构，使得合成具有挑战性天然产品发现研究所（NPDI）是天然领域的专家。产品生产，将使用既定协议生产用于这些研究的 trtE。 NPDI 将运用他们在该领域的专业知识来提高生产效率。这些研究将提供数据。建立 trtE 作为抗隐孢子虫治疗的主要候选药物至关重要。该化合物对多种寄生虫具有高度活性，这些研究将为未来的研究奠定基础评估该化合物作为治疗由顶复门寄生虫引起的疾病的广谱治疗剂，但最关键的是隐孢子虫病，这是一种具有世界范围重要性的被忽视的疾病，目前还没有针对它的治疗方法。良好的治疗选择。