Developing inhibitors of Plasmodium Acetyl CoA Synthetase as new multistage antimalarials

2020年，全球约有2.41亿疟疾病例和62.7万人死亡。非洲在全球疟疾负担中所占比例高得不成比例。2020年，非洲大陆占疟疾病例的95%，疟疾死亡人数的96%。5岁以下儿童、孕妇、艾滋病毒/艾滋病患者和免疫力低下的人移居高传播率地区，感染疟疾和发展成严重疾病的风险更高。其中，5岁以下儿童占非洲疟疾死亡总数的80%。此外，疟疾对流行的国家的经济有负面影响，使儿童失学，成年人失学或工作，助长贫困循环，增加脆弱的卫生系统的压力。在过去五年中，疟疾发病率和死亡率的下降停滞不前，东南亚和非洲对目前护理标准的抵抗力正在上升。迫切需要用于治疗和预防的新的抗疟疾药物。我们小组与疟疾药物加速器(MALDA)的其他成员合作，最近证明了恶性疟原虫乙酰-辅酶A合成酶对疟疾寄生虫的生存至关重要。我们确定了两个干扰这种酶功能的分子，并有可能开发成治疗和预防疟疾感染的新药。然而，这两个分子的效力不够强，也不具备口服药物所需的特性。我们选择了这些分子中的一个进行优化，MMV019721。我们现在已经开发出性能更好的更有效的分子，可以口服给药，我们相信有可能进一步优化疟疾的新治疗方法。这项建议的目的是改善这类分子的性质，以根据疟疾风险药物(MMV)的延迟领先标准提供已宣布的延迟领先。这将需要我们优化该分子的多种功能，包括它杀死疟疾寄生虫的能力，它到达寄生虫所在的身体部位而不被分解的能力，以及它的安全性。在该项目结束时，晚期铅将准备进入更多高级毒理学研究，然后进入人体临床试验。

There were approximately 241 million cases of malaria and 627,000 deaths worldwide in 2020. Africa carries a disproportionally high share of the global malaria burden. In 2020, the African continent accounted for 95% of malaria cases and 96% of malaria deaths. Children under 5 years of age, pregnant women, patients with HIV/AIDS and people with low immunity moving to areas with high level of transmission are a higher risk of contracting malaria and developing severe disease. Among those, children under 5 years account for 80% of all malaria deaths in Africa. In addition, malaria has a negative impact in the economy of countries where is endemic, keeping children out of school and adults out or work, contributing the cycle of poverty and increasing pressure in fragile health systems. In the past five years the reduction in malaria incidence and mortality has stalled and resistance to the current standard of care is rising in southeast Asia and Africa. There is an urgent need for new antimalarial agents for treatment and prophylaxis. Our group, in collaboration with other members of the Malaria Drug Accelerator (MalDA), have recently demonstrated that the enzyme P. falciparum acetyl-CoA synthetase is essential for the survival of malaria parasites. We identified two molecules that interfere with the function of this enzyme and have the potential to be developed into new medicines for the treatment and prevention of malaria infections. However, these two molecules are not sufficiently potent and do not have the properties required for an oral drug. We selected for optimisation one of these molecules, MMV019721. We have now developed more potent molecules with improved properties that can be dosed orally, and we are confident of the potential for further optimisation towards a new treatment for malaria. The aim of this proposal is to improve the properties of this class of molecules to deliver a declared late lead according to the Medicines for Malaria Venture (MMV) Late Lead Criteria. This will require us to optimise multiple features of the molecule including its ability to kill the malaria parasite, its ability to reach the site of the body where the parasite resides without being broken down and its safety. At the end of the project the late lead will be ready to enter more advance toxicological studies before moving into human clinical trials.