Development of next generation anti-malarials targeting the essential parasite protein kinase PfCLK3

开发针对重要寄生虫蛋白激酶 PfCLK3 的下一代抗疟疾药物

• 批准号: MR/T030569/1
• 负责人: Andrew Tobin
• 金额: $ 87.7万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT030569%2F1
• 关键词: Development; next; generation; anti; malarials

Despite the success of initiatives such as roll back malaria which have distributed millions of insecticide-impregnated bed nets and effective drug treatments for malaria including artemisinin combination therapies malaria still affects over 200 million people worldwide and is the cause of nearly 0.5 million deaths per annum. These figures alone might be enough to justify continued efforts to find new malaria drug treatments but more alarmingly is the fact that resistance to the current frontline treatments is now emerging which means that we are in a race to develop the next generation of drugs. This grant is designed as a pre-clinical drug discovery programme. The aim is to develop early stage drugs that can offer the potential of curing the symptoms of malaria but also importantly to prevent transmission of malaria from one person to another. The way that drugs are developed against malaria is to have the backing and support of key malaria drug discovery organisations. This includes the Bill and Melinda Gates Foundation, Medicines for Malaria Venture (MMV) and the Malaria Drug Accelerator (MalDa). It is through these organisations that drugs are ultimately developed for clinical trails. This grant is aimed at generating novel molecules that can then be used by these organisations to develop into drugs that can be tested in patients. We will do this by screening hundreds of thousands of compounds to discover molecules that inhibit our target protein called PfCLK3. We already know that molecules that inhibit the protein PfCLK3 rapidly kill the malaria parasite in a way that leads us to believe that drugs can be developed that target this protein. Once we have discovered molecules that inhibit PfCLK3 and kill the parasites we will develop these so-called hits to have properties that are necessary if they are to be effective and safe drugs. At the end of the grant we aim to have developed these hits to a sufficient extent to be fed into the MMV/Gates drug development pipeline. Such a programme is described as a hit to lead drug discovery programme and is an essential phase before further development of the lead compounds to drug candidates that can be used in trials on patients.

尽管诸如减少疟疾等倡议取得了成功，分发了数百万顶浸有杀虫剂的蚊帐和有效的疟疾药物治疗，包括青蒿素综合疗法，但疟疾仍然影响着全世界2亿多人，每年造成近50万人死亡。仅这些数字就足以证明继续努力寻找新的疟疾药物治疗方法是合理的，但更令人担忧的是，目前一线治疗方法的耐药性正在出现，这意味着我们正在竞相开发下一代药物。该补助金旨在作为临床前药物发现计划。其目的是开发早期药物，这些药物可以提供治愈疟疾症状的潜力，但也重要的是防止疟疾从一个人传播到另一个人。开发抗疟疾药物的方式是得到主要疟疾药物发现组织的支持和支持。这包括比尔和梅林达·盖茨基金会、疟疾新药研发公司和疟疾药物加速器。正是通过这些组织，药物最终被开发用于临床试验。这笔赠款旨在产生新的分子，然后这些组织可以使用这些分子开发成可以在患者身上进行测试的药物。我们将通过筛选数十万种化合物来发现抑制我们的靶蛋白PfCLK 3的分子。我们已经知道，抑制蛋白质PfCLK 3的分子可以迅速杀死疟原虫，这使我们相信可以开发针对这种蛋白质的药物。一旦我们发现了抑制PfCLK 3并杀死寄生虫的分子，我们将开发这些所谓的命中物，使其具有必要的特性，如果它们是有效和安全的药物。在赠款结束时，我们的目标是开发这些命中到足够的程度，以输入到MMV/盖茨药物开发管道。这样一个计划被描述为一个成功的领先药物发现计划，是进一步开发先导化合物成为可用于患者试验的候选药物之前的一个重要阶段。

项目成果

Investigating the Structure-Activity Relationship of 1,2,4-Triazine G-Protein-Coupled Receptor 84 (GPR84) Antagonists.

• DOI: 10.1021/acs.jmedchem.2c00804
• 发表时间: 2022-08-25
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Mahindra, Amit;Jenkins, Laura;Marsango, Sara;Huggett, Mark;Huggett, Margaret;Robinson, Lindsay;Gillespie, Jonathan;Rajamanickam, Muralikrishnan;Morrison, Angus;McElroy, Stuart;Tikhonova, Irina G.;Milligan, Graeme;Jamieson, Andrew G.
• 通讯作者: Jamieson, Andrew G.