ICF: Lead Optimisation of a Series of Antimalarial Plasmepsin IX/X Beta-hydroxyethylamine Based Inhibitors

ICF：一系列抗疟 Plasmepsin IX/X Beta-羟乙胺抑制剂的先导优化

• 批准号: MR/Y008774/1
• 负责人: Paul ONeill
• 金额: $ 143.4万
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY008774%2F1
• 关键词: ICF; Lead; Optimisation; Series; Antimalarial

Although there have been positive advances in the treatment of malaria, it remains a serious threat to global health, with 619,000 fatalities occurring worldwide (>90% in Africa) in 2021. These facts, combined with a threat of extended geographical malaria transmission due to climate change and increasing parasitic resistance towards available drugs , underline the importance in discovering new anti-malarial therapeutics with novel modes of action. In addition to drug resistance, significant drug attrition in the discovery phases of antimalarial drug development has occurred within the Medicines for Malaria Venture (MMV)'s portfolio over the last 5 years. (MMV is a not-for-profit public-private partnership, founded in 1999, with the mission to reduce the burden of malaria by the development of novel antimalarial drugs.)Malaria is a disease that is transmitted by the bite of the female Anopheles mosquito and is caused by a parasite belonging to Plasmodium genus. One of the challenges in drug treatment of this parasite is its complex life cycle which involves development in the mosquito, and two separate stages of development within the liver and red blood cells of the human host. Finding drug molecules that can target the parasite at all three development stages is the holy grail of antimalarial drug discovery since this will enable an highly effective antimalarial "triple-hit" to be exerted. Recently, two enzymes have been characterised known as Plasmepsins IX and X. These enzymes have been shown to be key to the parasite development in mosquito, blood and liver stages; inhibition of these proteins not only prevents the parasite invading human red blood cells but inhibition of plasmepsin X prevents the parasite from escaping the human red blood cell to continue the infection cycle. Recently, a breakthrough was made that showed a class of drug known as a protease inhibitor can inhibit these enzymes. This class of drug, which are chemically related to the HIV protease inhibitor drugs used for over two decades, have excellent parasite killing activity in test-tube experiments in the laboratory. More recently, one of these prototype drugs was shown to cure mice infected with Plasmodium species demonstrating the potential for development of an oral treatment of malaria infected human patients. Given the broad acting nature of these new parasite inhibitors, medicinal chemists have the opportunity to develop a novel drug with potential for malaria treatment, mosquito transmission blocking and for prevention (also known as chemoprophylaxis). A molecule with such properties would be highly valuable in the clinic. The aim of the research is to improve the prototype inhibitor by chemical modification of the scaffold to increase parasite killing activity as well as increasing drug stability within the human body. Ideally the drug treatment should be capable of curing malaria in a single or three daily doses treatment regimen. The project will use computational modelling, chemical synthesis and biological screening, as well as measurement and modelling of the metabolism of modified drugs to predict the drug exposures in humans. The aim is to obtain a molecule for preclinical profiling en route to a clinical trial in human inside 5 years. The programme is a multinational programme involving researchers in the UK (University of Liverpool, Imperial College, Liverpool School of Tropical Medicine), Italy (University of Milan) and Switzerland (MMV, University of Geneva).

尽管疟疾治疗取得了积极进展，但它仍然是对全球健康的严重威胁，2021年全球有619，000人死亡（>90%在非洲）。这些事实，加上气候变化造成的疟疾地理传播范围扩大的威胁和寄生虫对现有药物的抗药性增加，强调了发现具有新作用模式的新抗疟疾疗法的重要性。除耐药性外，在过去5年中，疟疾新药研发公司（MMV）的产品组合在抗疟药物开发的发现阶段也出现了重大的药物流失。(MMV是一个非营利的公私合作伙伴关系，成立于1999年，其使命是通过开发新型抗疟药物来减轻疟疾负担。疟疾是一种通过雌性按蚊叮咬传播的疾病，由属于疟原虫属的寄生虫引起。这种寄生虫的药物治疗的挑战之一是其复杂的生命周期，涉及蚊子的发育，以及人类宿主的肝脏和红细胞内的两个独立的发育阶段。找到能够在所有三个发育阶段靶向寄生虫的药物分子是抗疟药物发现的圣杯，因为这将使高效的抗疟“三重打击”得以发挥。最近，两种酶被鉴定为Plasmepsin IX和X。这些酶已被证明是蚊子，血液和肝脏阶段寄生虫发育的关键;抑制这些蛋白质不仅可以防止寄生虫侵入人类红细胞，而且抑制plasmepsin X可以防止寄生虫逃离人类红细胞继续感染周期。最近，一项突破性进展表明，一类被称为蛋白酶抑制剂的药物可以抑制这些酶。这类药物在化学上与使用了二十多年的艾滋病毒蛋白酶抑制剂药物有关，在实验室的试管实验中具有极好的寄生虫杀灭活性。最近，这些原型药物中的一种显示出治愈感染疟原虫物种的小鼠，这表明开发疟疾感染人类患者的口服治疗的潜力。鉴于这些新的寄生虫抑制剂的广泛作用性质，药物化学家有机会开发一种具有治疗疟疾、阻断蚊子传播和预防（也称为化学预防）潜力的新药。具有这种性质的分子在临床上将是非常有价值的。该研究的目的是通过对支架进行化学修饰来改善原型抑制剂，以增加寄生虫杀灭活性并增加药物在人体内的稳定性。理想情况下，药物治疗应该能够在单次或三次每日剂量治疗方案中治愈疟疾。该项目将使用计算建模、化学合成和生物筛选以及对改性药物代谢的测量和建模，以预测人体中的药物暴露。目的是在5年内获得用于临床前分析的分子，以进行人体临床试验。该方案是一个多国方案，涉及英国（利物浦大学、帝国理工学院、利物浦热带医学院）、意大利（米兰大学）和瑞士（MMV、日内瓦大学）的研究人员。