Defining the mechanism of action of the 8-aminoquinolines: A pre-requisite to rationally designed safe antimalarials for the elimination era

疟疾影响约5亿人，每年导致近100万人死亡，主要是五岁以下的非洲儿童。消除疟疾方案在一些国家取得了成功，其雄心是在未来几年将这些方案推广到更多的国家。消除疟疾方案的一个重要内容是拥有能够治愈复发疟疾的药物(通过杀死感染并持续存在于肝脏中的疟疾寄生虫)以及能够阻断疾病传播的药物(通过杀死传播到蚊子宿主并在其体内生活的阶段)。只有一类抗疟疾药物(称为8-氨基喹啉)具有这些理想的特性，这类药物中有一种注册药物名为伯马喹，另一种名为他苯喹的新衍生药(剂量方案得到改进)目前正在进行临床试验。然而，不幸的是，这两种药物对患有遗传性疾病(称为葡萄糖-6-磷酸脱氢酶缺乏症)的人都有潜在的致命性，这种疾病影响着全球约4亿人，特别是来自疟疾流行国家的人。因此，迫切需要一种比伯喹更安全的替代品，这一问题被疟疾药物风险投资组织(MMV，为新的抗疟疾药物提供资金的全球组织)、Malera全球研究联盟(一个由国际科学家和政策制定者组成的联盟，制定了消除疟疾的优先事项)和世界卫生组织(WHO)确定为优先事项。提高药物安全性或有效性的一种通常具有成本效益和快速的方法是了解当前药物的作用机制和毒性，然后产生具有改进性质的衍生物，例如在第二代抗生素的生成中。然而，尽管伯喹已经使用了60多年，但我们到目前为止还不知道这种药物是如何起作用的，这严重阻碍了生产更安全的衍生品的努力。在这里，我们提供了我们的初步数据，表明两种寄生虫酶(称为PfCPR和PfFNR)参与了伯喹的作用模式。我们相信，我们将能够利用这些知识来生产更安全的伯喹衍生品。然而，一个新的药物发现计划是非常昂贵和劳动密集型的，在我们可以继续进行之前，我们需要这两种酶在伯喹作用模式中所起作用的确凿证据。因此，该MRC拨款申请建议使用最新的分子生物学技术和实验性疾病模型(使用人源化肝脏的小鼠)来生成确凿的证据，然后为药物发现项目的后续研究提供支持。这项应用的研究人员在工作时间表中列出的技术和方法方面拥有丰富的经验，我们还将与工业界(GSK)和学术界合作，以提供该领域最新进展和技术的支持。利物浦队在将本文所述的基础研究转化为新一代改进疗法方面有着良好的记录。该项目已经与MMV和GSK进行了讨论，这两家公司都完全支持这项研究的需要、所使用的方法和翻译的潜力，以满足这一紧迫的医疗需求。

Malaria affects some 0.5 billion people and results in nearly 1 million deaths each year, mainly African children under the age of five. Malaria elimination programmes have been successful in some countries and the ambition is to roll these out to many more countries in the coming years. An important element in malaria elimination programmes is to have drugs that are able to cure relapse malaria (by killing the malaria parasite that infects and persists in the liver) as well as drugs that are able to block the transmission of the disease (by killing the stages that are transmitted to and live in the mosquito host). There is only one class of antimalarial drugs (known an 8-aminoquinolines) with these desired properties, with one registered drug from this class known as primaquine and a new derivative called tafenoquine (with an improved dosing regimen) that is currently in clinical trials. Unfortunately however, both drugs are potentially lethal to people with a genetic disorder (known as Glucose-6-phosphate dehydrogenase deficiency) that affects some 400 million people word-wide, especially people from malaria endemic countries. A safer alternative to primaquine is therefore urgently required and this issue as been identified as a priority by the Medicines for Malaria Venture (MMV, the global organization that funds new antimalarial drugs), the malERA global study consortium (a consortium of international scientists and policy makers that set out the priorities towards malaria elimination) and by the World Health Organization (WHO). An often cost-effective and rapid way of improving the safety or efficacy of drugs is to understand the mechanism of action and toxicity of current drugs and then generate derivatives with improved properties, e.g. such as in the generation of second-generation antibiotics. However, despite the fact that primaquine has been used for over 60 years, we hitherto do not know how this drug works, severely hampering efforts to generate safer derivatives. Here we present our initial data that indicates the involvement of two parasite enzymes (known as PfCPR and PfFNR) in the mode of action of primaquine. We are confident that we will be able to use this knowledge to generate safer derivatives of primaquine. However, a new drug discovery programme is very expensive and labour intensive and before we can go ahead we need definitive proof for the role of these two enzymes in the mode of action of primaquine. This MRC grant application therefore proposes to use the very latest molecular biology techniques and experimental disease models (using mice with humanized livers) to generate the definitive proof that will then allow follow-on research for a drug discovery project. The researchers on this application have extensive experience in the techniques and approaches set out in the schedule of work, and we will also collaborate with industry (GSK) and academia to provide support with the very latest advancements and technologies in the field. The Liverpool team have a track record in translating basic research such as that described here into the generation of improved therapies. The project has been discussed with MMV and GSK, both of who are fully supportive of the need of the study, the approach used and the potential for translation to meet this urgent medical need.