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

定义 8-氨基喹啉的作用机制：消除时代合理设计安全抗疟药的先决条件

• 批准号: MR/L000644/1
• 负责人: Giancarlo Biagini
• 金额: $ 66.02万
• 依托单位: Liverpool School of Tropical Medicine
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL000644%2F1
• 关键词: Defining; mechanism; action; aminoquinolines; pre

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.

疟疾每年影响约 5 亿人，导致近 100 万人死亡，其中主要是五岁以下的非洲儿童。消除疟疾计划在一些国家取得了成功，我们的目标是在未来几年将这些计划推广到更多国家。消除疟疾计划的一个重要组成部分是拥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疾寄生虫）以及能够阻止疾病传播的药物（通过杀死传播到蚊子宿主并在其体内生存的阶段）。只有一类抗疟药物（称为 8-氨基喹啉）具有这些所需的特性，该类药物中的一种已注册药物称为伯氨喹，另一种称为他非诺喹的新衍生物（具有改进的给药方案）目前正处于临床试验阶段。然而不幸的是，这两种药物对于患有遗传性疾病（称为 6-磷酸葡萄糖脱氢酶缺乏症）的人来说可能是致命的，这种遗传性疾病影响着全世界约 4 亿人，尤其是来自疟疾流行国家的人们。因此，迫切需要一种更安全的伯氨喹替代品，疟疾药​​物风险投资公司（MMV，资助新抗疟疾药物的全球组织）、malERA 全球研究联盟（由国际科学家和政策制定者组成的联盟，制定消除疟疾的优先事项）和世界卫生组织 (WHO) 已将这一问题确定为优先事项。提高药物安全性或功效的一种通常具有成本效益且快速的方法是了解现有药物的作用机制和毒性，然后生成具有改进特性的衍生物，例如例如第二代抗生素的产生。然而，尽管伯氨喹已经使用了 60 多年，但我们迄今为止还不知道这种药物是如何发挥作用的，这严重阻碍了生产更安全衍生物的努力。在这里，我们提出了初步数据，表明两种寄生虫酶（称为 PfCPR 和 PfFNR）参与了伯氨喹的作用模式。我们相信，我们将能够利用这些知识来生产更安全的伯氨喹衍生物。然而，新药发现计划非常昂贵且劳动密集型，在我们继续进行之前，我们需要明确的证据来证明这两种酶在伯氨喹作用模式中的作用。因此，这项 MRC 拨款申请建议使用最新的分子生物学技术和实验疾病模型（使用具有人源化肝脏的小鼠）来生成明确的证据，以便为药物发现项目进行后续研究。该应用的研究人员在工作计划中规定的技术和方法方面拥有丰富的经验，我们还将与工业界（葛兰素史克）和学术界合作，提供该领域最新进展和技术的支持。利物浦团队在将基础研究（例如本文所述）转化为改进疗法方面拥有良好的记录。该项目已与 MMV 和 GSK 进行了讨论，两家公司都完全支持该研究的需求、所使用的方法以及转化的潜力，以满足这一紧迫的医疗需求。

项目成果

Rapid kill of malaria parasites by artemisinin and semi-synthetic endoperoxides involves ROS-dependent depolarization of the membrane potential.

• DOI: 10.1093/jac/dkt486
• 发表时间: 2014-04
• 期刊: The Journal of antimicrobial chemotherapy
• 作者: Antoine T;Fisher N;Amewu R;O'Neill PM;Ward SA;Biagini GA
• 通讯作者: Biagini GA

OptiMal-PK: an internet-based, user-friendly interface for the mathematical-based design of optimized anti-malarial treatment regimens.

• DOI: 10.1186/s12936-016-1401-8
• 发表时间: 2016-07-07
• 期刊: Malaria journal
• 影响因子: 3
• 作者: Aljayyoussi G;Kay K;Ward SA;Biagini GA
• 通讯作者: Biagini GA

Pharmacokinetic-Pharmacodynamic modelling of intracellular Mycobacterium tuberculosis growth and kill rates is predictive of clinical treatment duration.

• DOI: 10.1038/s41598-017-00529-6
• 发表时间: 2017-03-29
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Aljayyoussi G;Jenkins VA;Sharma R;Ardrey A;Donnellan S;Ward SA;Biagini GA
• 通讯作者: Biagini GA