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）

• 批准号: 10495750
• 负责人: ROBERTA M O'CONNOR
• 金额: $ 42.92万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 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/10495750
• 关键词: Development; new; marine; natural; product

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 没有有效治疗隐孢子虫的有效疗法，这是一种寄生虫，现在已被识别 作为全世界腹泻病的重要原因，也是定义病原体的重要辅助。在此过程中 海洋共生细菌产生的抗寄生虫活性的采矿化合物，我们确定了 化合物，Tartrolon E（TRTE），可能抑制隐孢子虫的体外生长以及几个 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。实际上，TRTE的有效性更高10倍 与报道的最有效化合物相比 日期，也是唯一拥有广泛抗疾病疗法的承诺的化合物。这些 观察强烈鼓励进一步探索TRTE治疗的临床潜力 隐孢子虫病。在此处提出的研究中，我们将检验以下假设：TRTE具有活性 通过完成以下内容，必须成为候选候选疗法以治疗隐孢子虫病 目的：目标1：评估TRE的规格特异性和生命周期阶段的特异性 隐孢子虫。将对C. parvum场分离株和hominis和TRTE的活性测试TRTE 目标2：优化TRTE剂量 方案。将进行药物动力学（A），药代动力学（B）和生物利用度（C）研究 设计最佳治疗策略。目标3：评估TRTE对隐孢子虫的效率 在严重的免疫抑制和反刍动物的反刍动物模型中感染。一个。 我们将测试TRTE抑制和消除NOD-SCIDγ小鼠中隐孢子虫感染的能力。 B 由于小鼠没有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 和新生儿羔羊的腹泻病。目标4：优化从teredinibacter的TRTE生产 TRENNERE T7901：像许多天然产品一样，TRTE具有复杂的结构，可以使综合挑战挑战 并禁止昂贵。天然产品发现研究所（NPDI），自然领域的专家 产品生产将使用已建立的方案为这些研究生产TRTE。在此过程中， NPDI将在该领域应用其专业知识来提高生产效率。这些研究将提供数据 将TRTE作为抗晶状体孢子虫治疗的主要候选者必不可少。而且，因为这个 化合物对多个寄生虫具有很高的活跃性，这些研究将支持未来的研究 评估该化合物作为由寄生虫引起的疾病的广泛谱疗法， 但是，对于隐孢子虫病而言，最严重的是一种被忽视的全球意义疾病，没有 良好的治疗选择。