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(申请人提供)：抗疟疾血液期药物的发现和开发势头良好，但迫切需要抗疟疾其他阶段的新化合物。由于消灭疟疾的目标现在处于中心位置，将需要有效对抗疟疾肝脏阶段的新药，特别是休眠的间日疟原虫和卵形疟原虫的催眠虫。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疾药物，对催眠虫和其他红外期寄生虫具有高效的疗效。这项提案的目标是鉴定RC-12的活性代谢物，这是追求这一目标的第一步，RC-12使其在金标准催眠体动物模型-食蟹猴感染猕猴中具有高效的化学型。我们的中心假设是，物种特异性代谢解释了RC-12对恒河猴食蟹猴嗜食性支原体催眠虫的高效和对人类间日疟原虫催眠虫缺乏效力之间的二分法。这一假设是基于我们实验室提供的初步数据而产生的。这项研究的基本原理是提供工具，开始阐明RC-12的药代动力学/药效学(PK/PD)，并为药物发现确定新的线索(活性代谢物)。为此，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种可能的人、猴子和大鼠RC-12细胞色素P450代谢物，以确定其指定的结构；2)建立RC-12的代谢和药代动力学基线；3)评估RC-12及其CYP450代谢物在恒河猴和人肝细胞中对食蟹猴嗜睡虫活性的影响。我们的方法是创新的，因为RC-12的代谢和PK从未被研究过，我们建议使用恒河猴和人类肝细胞将有效地剖析宿主代谢与原生动物物种复合易感性的差异，而不使用间日疟原虫。这项工作的预期成果如下。首先，我们将对RC-12的CYP450代谢有一个透彻的了解。其次，我们将鉴定RC-12的一种或多种活性代谢物。第三，我们将首次为RC-12生成PK数据。我们认为，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活性抗疟疾药物提供基础，该药物对间日疟原虫和卵形疟原虫具有高效的治疗作用。 催眠虫和其他红外期寄生虫通过我们对RC-12的PK/PD谱的了解而得知。