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。根据最新的《世界疟疾报告(2020年)》，2019年有2.29亿疟疾病例，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，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(已知为8-氨基喹啉)注册具有这些预期的性质，即伯喹(PQ)和他苯喹(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，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。出于我们不理解的原因，TQ已被证明比PQ更安全。鉴于TQ已改进了安全功能，计划在不久的将来取代PQ。然而，不幸的是，在最近的一项临床试验中，TQ与目前的一线抗疟疾药物(称为青蒿素联合疗法，ACTS)联合使用时，未能防止疟疾复发。最近的这一发现是一个重大的公共卫生问题，关键是我们不了解其中的原因。该项目旨在更深入地了解TQ和相关药物的作用模式，以便我们能够快速找到有效对抗抗药性疟疾寄生虫且不会对TQ的疗效产生不利影响的合适的组合伙伴。在最近的一项研究中，我们能够在该药物类别的70年历史上首次展示该药物类别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。这项MRC赠款申请建议使用最新的生物技术和实验平台来生成确切的证据，解释我们模型第一步背后的机制。这些信息将使社区能够部署有效的TQ联合疗法，以防止疟疾复发，并对大多数抗药性疟疾寄生虫有效。此外，我们希望从我们的研究中获得的信息将有可能为第二代药物的设计提供信息，这些药物已经改善了疗效和安全性。为了实现我们宣布的目标，我们组建了一支具有广泛疟疾治疗经验和专业知识的国际多学科研究团队，对这一抗疟疾药物类别具有专门知识。这不仅将确保研究的成功执行，而且还将确保基础科学成果有可能转化为患者和生活在疟疾流行国家的人民的切实利益--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