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

尽管在治疗疟疾方面取得了积极进展，但它仍然是对全球健康的严重威胁，2021年全世界有61.9万人死亡(90%在非洲)。这些事实，再加上气候变化造成的疟疾地理传播扩大的威胁，以及对现有药物越来越多的寄生虫耐药性，突显了以新的行动模式发现新的抗疟疾疗法的重要性。除了耐药性之外，在过去5年中，S的抗疟疾药风险投资组合中还出现了抗疟疾药物开发的发现阶段的重大药物损耗。(MMV是一个非营利性的公私伙伴关系，成立于1999年，其使命是通过开发新的抗疟疾药物来减轻疟疾的负担。)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面临的挑战之一是它复杂的生命周期，包括蚊子的发育，以及人类宿主肝脏和红细胞内的两个不同的发育阶段。找到在所有三个发育阶段都能针对寄生虫的药物分子是抗疟疾药物发现的圣杯，因为这将使高效的抗疟疾“三重打击”得以发挥作用。最近，两种酶被鉴定为纤溶酶IX和X。这些酶被证明是寄生虫在蚊子、血液和肝脏阶段发展的关键；抑制这些蛋白不仅可以防止寄生虫入侵人类红细胞，而且抑制纤溶酶X可以防止寄生虫逃离人类红细胞继续感染循环。最近，一项突破性的发现表明，一种名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20多年的HIV蛋白酶抑制剂药物有关，在实验室的试管实验中具有良好的寄生虫杀灭活性。最近，其中一种原型药物被证明可以治愈感染疟疾物种的小鼠，展示了开发一种口服疗法治疗感染疟疾的人类患者的潜力。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新的药物，具有治疗疟疾、阻断蚊子传播和预防(也称为化学预防)的潜力。具有这种性质的分子将在临床上具有很高的价值。这项研究的目的是通过对支架进行化学修饰来改进原型抑制剂，以增加寄生虫的杀灭活性以及增加人体内药物的稳定性。理想情况下，药物治疗应该能够以每日一次或三次剂量的治疗方案治愈疟疾。该项目将使用计算机建模、化学合成和生物筛选，以及对修饰药物的新陈代谢进行测量和建模，以预测人体内的药物暴露。其目的是在5年内获得一种用于临床前分析的分子，并在人体上进行临床试验。该计划是一个多国计划，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。

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).