MICA: Defining the two-step relay mechanism of action of the 8-aminoquinolines: A precondition for optimal combination therapies for relapse malaria

全球承诺消除/根除疟疾，但尽管在过去十年中取得了重大进展，疟疾发病率和死亡率仍然高得令人无法接受。根据最新发布的《世界疟疾报告（2020年）》，2019年全球共有2.29亿例疟疾病例，估计疟疾死亡人数为40.9万人。消除疟疾方案在一些国家取得了成功，目标是在未来几年将这些方案推广到更多的国家。消灭疟疾方案的一个重要内容是要有能够治愈疟疾复发的药物（通过杀死感染并持续存在于肝脏中的疟原虫）以及能够阻断疾病传播的药物（通过杀死传播给蚊子宿主并生活在蚊子宿主中的阶段）。只有一类抗疟疾药物（已知的8-氨基喹啉）具有这些期望的特性，伯氨喹（PQ）和他非诺喹（TQ）。PQ对患有遗传性疾病（称为葡萄糖-6-磷酸脱氢酶缺乏症）的人具有潜在的致命性，该疾病影响了全球约4亿人，特别是来自疟疾流行国家的人。由于我们不理解的原因，TQ已被证明比PQ更安全。鉴于TQ已改进安全功能，计划在不久的将来将TQ取代PQ。然而，不幸的是，在最近的一项临床试验中，TQ与目前的一线抗疟药物（称为青蒿素综合疗法）联合使用时未能预防疟疾复发。最近的这一发现是一个重大的公共卫生问题，关键是我们不明白其中的原因。该项目旨在更深入地了解TQ和相关药物的作用模式，以便我们能够快速识别合适的组合伙伴，这些组合伙伴对抗药性疟疾寄生虫具有活性，并且不会对TQ的疗效产生不利影响。在最近的一项研究中，我们能够在该类药物70年的历史中首次展示该类药物如何杀死疟疾寄生虫。我们提出的模型是一个两步模型。虽然我们认为这类药物在模型的第二步中具有相同的作用机制，但我们认为在模型的第一步中药物类别之间存在差异。该MRC资助申请建议使用最新的生物技术和实验平台来产生明确的证据，解释我们模型第一步的机制。这些信息将使社区能够部署有效的TQ组合疗法，预防疟疾复发，并对大多数抗药性疟疾寄生虫有效。此外，我们希望我们从研究中获得的信息将有可能为设计具有更好疗效和安全性的第二代药物提供信息。为了实现我们的既定目标，我们组建了一个国际和多学科的研究人员团队，他们在疟疾治疗方面拥有丰富的经验和专业知识，并对这类抗疟药物有专门的了解。这不仅将确保研究的成功实施，而且还将确保基础科学成果有可能转化为生活在疟疾流行国家的患者和人民的实际利益--这是我们所有工作的最终目标

There is a global commitment to the elimination/eradication of malaria but despite significant advances in the last decade, malaria morbidity and mortality remains unacceptably high. According to the latest World malaria report (2020), there were 229 million cases of malaria in 2019, with an estimated number of malaria deaths at 409,000. 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) that are registered with these desired properties, primaquine (PQ) and tafenoquine (TQ). PQ is 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. For reasons that we do not understand, TQ has been shown to be safer than PQ. Given that TQ has improved safety features, it was planned that TQ would replace PQ in the near future. Unfortunately however, in a recent clinical trial, TQ failed to prevent relapse malaria when administered in combination with current first-line antimalarials (known as artemisinin combination therapies, ACTs). This recent finding is a major public health concern and critically we do not understand the reason for this. This project sets out to gain a deeper understanding of the mode of action of TQ and related drugs so that we can rapidly identify suitable combination partners that are active against drug resistant malaria parasites and will not adversely affect the efficacy of TQ.In a recent study we were able for the first time in the 70 year history of this drug class, to show how this drug class kills malaria parasites. The model that we proposed is a two-step model. Whilst we believe that all drugs from this class share the same mechanism of action in the second step of the model, we believe that there are differences among the drug class in the first step of the model. This MRC grant application proposes to use the very latest biological techniques and experimental platforms to generate the definitive evidence that explains the mechanisms underlying the first step of our model. This information will then allow the community to deploy effective TQ combination therapies that prevent relapse malaria and that are effective against the majority of drug resistance malaria parasites. In addition, we hope that the information we generate from our studies will have the potential to inform the design of second generation drugs that have improved efficacy and safety profiles.Towards achieving our stated goal, we have assembled an international and multidisciplinary team of researchers with extensive experience and expertise in malaria therapeutics, with specific knowledge of this antimalarial drug class. This will not only ensure the successful execution of the study, but it will also ensure that the basic science outputs have the potential to be translated to tangible benefits to patients and people living in malaria-endemic countries - the ultimate goal of all of our work