Leveraging RC-12 for Radical Cure of Plasmodium Vivax

利用 RC-12 根治间日疟原虫

• 批准号: 8430756
• 负责人: Jonathan L Vennerstrom
• 金额: $ 21.29万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8430756
• 关键词: Accounting; Aminoquinolines; Animal Model; Animals; Antimalarials; Blood; Cessation of life; Chemistry; Data; Disease; Dose; Drug Kinetics; Feedback; G6PD gene; Goals; Gold; Half-Life; Hemolysis; Hepatic; Hepatocyte; Human; Incidence; Knowledge; Laboratories; Lead; Liver; Liver Microsomes; Macaca mulatta; Malaria; Metabolic; Metabolism; Methemoglobinemia; Microsomes; Mission; Monkeys; Outcome; Parasites; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Plasmodium vivax; Predisposition; Pregnancy; Primaquine; Protozoa; Public Health; Rattus; Research; Staging; Structure; Testing; Time; Work; base; chemotherapy; drug development; drug discovery; innovation; public health relevance; tool

DESCRIPTION (provided by applicant): There is good momentum in the discovery and development of drugs active against the blood stage of malaria, but new compounds active against other stages of malaria are sorely needed. As the goal of malaria eradication is now on center stage, new drugs active against the liver stage of malaria, most particularly the dormant hypnozoites of Plasmodium vivax and P. ovale will be required. Our long-term goal is to leverage RC-12 to discover a new orally active single-dose antimalarial drug with high efficacy against hypnozoites and other exoerythrocytic stage parasites. The objective of this proposal, the first step in pursuit of this goal, is to identify the active metabolites of RC-12 that endow tis chemotype with its high efficacy in the 'gold-standard' hypnozoite animal model - P. cynomolgi-infected rhesus monkeys. Our central hypothesis is that species-specific metabolism accounts for the dichotomy between the high efficacy of RC-12 against P. cynomolgi hypnozoites in rhesus monkeys and the lack of efficacy of RC-12 against P. vivax hypnozoites in humans. This hypothesis arose on the basis of preliminary data produced in our laboratories. The rationale that underlies this research is to provide tools to begin to elucidate the pharmacokinetics/pharmacodynamics (PK/PD) of RC-12 and to identify new leads (active metabolites) for drug discovery. To do so, and to test our central hypothesis, we propose the following three specific aims: 1) To synthesize the nine putative human, monkey, and rat RC-12 CYP450 metabolites to confirm their assigned structures; 2) To establish a baseline metabolic and pharmacokinetic profile for RC-12; 3) To assess RC-12 and its CYP450 metabolites for activity against P. cynomolgi hypnozoites in both rhesus and human hepatocytes. Our approach is innovative because the metabolism and PK of RC-12 have never been studied and our proposed use of both rhesus and human hepatocytes will effectively dissect differences in host metabolism vs. protozoal species compound susceptibility without using P. vivax parasites. The expected outcomes from this work are as follows. First, we will achieve a thorough understanding of the CYP450 metabolism of RC-12. Second, we will identify one or more active metabolites of RC-12. Third, we will have, for the first time, generated PK data for RC-12. We assert that our proposed research is significant because it will provide the basis for the discovery of a new orally active antimalarial drug with high efficacy against P. vivax and P. ovale hypnozoites and other exoerythrocytic stage parasites informed by our knowledge of the PK/PD profile of RC-12.

描述（由申请人提供）：对疟疾血液阶段具有活性的药物的发现和开发势头良好，但迫切需要对其他阶段的疟疾具有活性的新化合物。由于根除疟疾的目标现已成为中心议题，因此需要针对疟疾肝期有效的新药物，尤其是间日疟原虫和卵形疟原虫的休眠子孢子。我们的长期目标是利用 RC-12 发现一种新的口服活性单剂量抗疟药，对休眠子和其他红细胞外期寄生虫具有高效作用。该提案的目标是实现这一目标的第一步，是确定 RC-12 的活性代谢物，这些代谢物赋予该化学型在“金标准”催眠动物模型（食蟹猴感染的恒河猴）中的高效能猴子。我们的中心假设是，物种特异性代谢解释了 RC-12 对恒河猴中食蟹猴休眠子的高效性和 RC-12 对人类间日疟原虫休眠子缺乏功效之间的二分性。这一假设是根据我们实验室产生的初步数据提出的。这项研究的基本原理是提供工具来阐明 RC-12 的药代动力学/药效学 (PK/PD)，并确定药物发现的新先导化合物（活性代谢物）。为此，并为了检验我们的中心假设，我们提出以下三个具体目标：1）合成九种假定的人类、猴子和大鼠 RC-12 CYP450 代谢物，以确认其指定的结构； 2) 建立RC-12的基线代谢和​​药代动力学特征； 3) 评估 RC-12 及其 CYP450 代谢物在恒河猴和人肝细胞中对抗食蟹猴休眠子的活性。我们的方法是创新的，因为从未研究过 RC-12 的代谢和 PK，并且我们建议使用恒河猴和人类肝细胞将有效剖析宿主代谢与原生动物物种化合物敏感性的差异，而无需使用间日疟原虫寄生虫。这项工作的预期成果如下。首先，我们将彻底了解 RC-12 的 CYP450 代谢。其次，我们将鉴定 RC-12 的一种或多种活性代谢物。第三，我们将首次生成 RC-12 的 PK 数据。我们断言，我们提出的研究意义重大，因为它将为发现一种新型口服活性抗疟药物奠定基础，该药物对间日疟原虫和卵形疟原虫具有高效作用 根据我们对 RC-12 PK/PD 特征的了解，我们可以了解休眠子和其他红细胞外阶段寄生虫。