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

MICA:定义 8-氨基喹啉的两步中继作用机制:复发性疟疾最佳联合疗法的先决条件

基本信息

  • 批准号:
    MR/W002248/1
  • 负责人:
  • 金额:
    $ 83.15万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2021
  • 资助国家:
    英国
  • 起止时间:
    2021 至 无数据
  • 项目状态:
    未结题

项目摘要

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
全球承诺消除/根除疟疾,但尽管过去十年取得了重大进展,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2.29亿例疟疾病例,估计疟疾死亡人数为40.9万人。消除疟疾规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规划推广到更多的国家。消除疟疾规划的一个重要内容是拥有能够治愈复发疟疾的药物(通过杀死感染并在肝脏中持续存在的疟疾寄生虫)以及能够阻止疾病传播的药物(通过杀死传播给蚊子宿主并在其体内生存的阶段)。只有一类抗疟疾药物(已知的8-氨基喹啉类药物)注册具有这些期望的特性,即伯氨喹和他非诺喹。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,全球约有4亿人受到这种疾病的影响,尤其是来自疟疾流行国家的人。由于我们不了解的原因,TQ已被证明比PQ更安全。鉴于TQ改进了安全功能,计划在不久的将来TQ将取代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)联合使用时未能预防疟疾复发。这一最新发现是一个重大的公共卫生问题,关键是我们不了解其原因。该项目旨在更深入地了解TQ和相关药物的作用模式,以便我们能够快速确定对耐药疟疾寄生虫有效且不会对TQ疗效产生不利影响的合适组合伙伴。在最近的一项研究中,我们首次能够在这类药物70年的历史中,展示这类药物是如何杀死疟疾寄生虫的。我们提出的模型是一个两步模型。虽然我们认为在模型的第二步中,这类药物的作用机制是相同的,但我们认为在模型的第一步中,这类药物之间存在差异。这项MRC拨款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。然后,这些信息将使社区能够部署有效的TQ联合疗法,防止疟疾复发并对大多数耐药疟疾寄生虫有效。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,这些药物具有更好的疗效和安全性。为了实现我们的既定目标,我们组建了一支国际多学科研究人员团队,他们在疟疾治疗方面具有丰富的经验和专业知识,对这类抗疟疾药物有专门的了解。这不仅将确保这项研究的成功实施,而且还将确保基础科学成果有可能转化为疟疾流行国家的患者和人民的切实利益——这是我们所有工作的最终目标

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Attaching protein-adsorbing silica particles to the surface of cotton substrates for bioaerosol capture including SARS-CoV-2.
  • DOI:
    10.1038/s41467-023-40696-x
  • 发表时间:
    2023-08-18
  • 期刊:
  • 影响因子:
    16.6
  • 作者:
    Collings, Kieran;Boisdon, Cedric;Sham, Tung-Ting;Skinley, Kevin;Oh, Hyun-Kyung;Prince, Tessa;Ahmed, Adham;Pennington, Shaun H.;Brownridge, Philip J.;Edwards, Thomas;Biagini, Giancarlo A.;Eyers, Claire E.;Lamb, Amanda;Myers, Peter;Maher, Simon
  • 通讯作者:
    Maher, Simon
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Giancarlo Biagini其他文献

A mycobacterial DNA extraction protocol designed for resource limited settings generates high quality whole genome sequencing
专为资源有限环境设计的分枝杆菌 DNA 提取方案可生成高质量的全基因组测序
  • DOI:
    10.1101/2024.05.31.596815
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Caitlin Percy;Ilinca Memelis;Thomas Edwards;Adam P. Roberts;Giancarlo Biagini;Daire M. Cantillon
  • 通讯作者:
    Daire M. Cantillon
Sex, power and drugs: the murky world of malaria parasite mitochondria
  • DOI:
    10.1186/1475-2875-13-s1-p11
  • 发表时间:
    2014-09-22
  • 期刊:
  • 影响因子:
    3.000
  • 作者:
    Giancarlo Biagini
  • 通讯作者:
    Giancarlo Biagini

Giancarlo Biagini的其他文献

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{{ truncateString('Giancarlo Biagini', 18)}}的其他基金

MRC IAA 2021 Liverpool School of Tropical Medicine
MRC IAA 2021 利物浦热带医学院
  • 批准号:
    MR/X502911/1
  • 财政年份:
    2022
  • 资助金额:
    $ 83.15万
  • 项目类别:
    Research Grant
Development of sustainable academic-industry partnerships: Untapping breakthrough innovation for the treatment and management of infectious diseases
发展可持续的学术与产业伙伴关系:为传染病的治疗和管理探索突破性创新
  • 批准号:
    MR/W004356/1
  • 财政年份:
    2021
  • 资助金额:
    $ 83.15万
  • 项目类别:
    Research Grant
MICA: New combination therapy against MDR TB targeting the respiratory chain
MICA:针对呼吸链的耐多药结核病新联合疗法
  • 批准号:
    MR/S00467X/1
  • 财政年份:
    2019
  • 资助金额:
    $ 83.15万
  • 项目类别:
    Research Grant
MICA: New combination therapy against MDR TB targeting the respiratory chain
MICA:针对呼吸链的耐多药结核病新联合疗法
  • 批准号:
    MC_PC_17225
  • 财政年份:
    2018
  • 资助金额:
    $ 83.15万
  • 项目类别:
    Intramural
Understanding pharmacokinetic - pharmacodynamic determinants of outcome to inform dose optimisation for non-MDR TB re-treatment patients in Vietnam
了解药代动力学 - 药效学结果的决定因素,为越南非耐多药结核病再治疗患者的剂量优化提供信息
  • 批准号:
    MR/N028376/1
  • 财政年份:
    2016
  • 资助金额:
    $ 83.15万
  • 项目类别:
    Research Grant
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
  • 财政年份:
    2014
  • 资助金额:
    $ 83.15万
  • 项目类别:
    Research Grant
LEAD SERIES DEVELOPMENT & OPTIMISATION OF A NEW DRUG AGAINST ACTIVE AND LATENT TUBERCULOSIS
铅系列开发
  • 批准号:
    G1002586/1
  • 财政年份:
    2011
  • 资助金额:
    $ 83.15万
  • 项目类别:
    Research Grant

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