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）：在发现和开发对疟疾的血液阶段有活性的药物方面有良好的势头，但迫切需要对疟疾的其他阶段有活性的新化合物。由于消灭疟疾的目标现在处于中心阶段，因此将需要对疟疾的肝脏阶段，特别是间日疟原虫和卵形疟原虫的休眠催眠虫具有活性的新药。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物，对催眠虫和其他红细胞外期寄生虫具有高疗效。该提案的目的是，追求这一目标的第一步，是鉴定RC-12的活性代谢物，其赋予其化学型在“金标准”催眠动物模型-食蟹猴疟原虫感染的恒河猴中的高功效。我们的中心假设是，种属特异性代谢解释了RC-12对猕猴中食蟹猴疟原虫催眠子的高功效与RC-12对人类中间日疟原虫催眠子缺乏功效之间的二分法。这一假设是根据我们实验室的初步数据提出的。本研究的基本原理是提供开始阐明RC-12的药代动力学/药效学（PK/PD）的工具，并确定药物发现的新线索（活性代谢物）。为了做到这一点，并检验我们的中心假设，我们提出了以下三个具体目标：1）合成9种假定的人、猴和大鼠RC-12 CYP 450代谢物，以确认其指定结构; 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CYP 450代谢物在恒河猴和人肝细胞中对食蟹猴疟原虫催眠子的活性。我们的方法是创新的，因为RC-12的代谢和PK从未被研究过，并且我们提出的使用恒河猴和人肝细胞将有效地剖析宿主代谢与原生动物物种化合物敏感性的差异，而不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CYP 450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，我们提出的研究是有意义的，因为它将为发现一种新的口服抗疟药物提供基础，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的PK/PD特征的了解，我们可以发现嗜眠原虫和其他红细胞外期寄生虫。