Developing inhibitors of Plasmodium Acetyl CoA Synthetase as new multistage antimalarials

开发疟原虫乙酰辅酶A合成酶抑制剂作为新型多级抗疟药

• 批准号: MR/X030202/1
• 负责人: Ian Gilbert
• 金额: $ 302.17万
• 依托单位: University of Dundee
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX030202%2F1
• 关键词: Developing; inhibitors; Plasmodium; Acetyl; CoA

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.

2020年，全球约有2.41亿例疟疾病例和62.7万例死亡。非洲在全球疟疾负担中所占的份额高得惊人。2020年，非洲大陆占疟疾病例的95%，占疟疾死亡人数的96%。5岁以下儿童、孕妇、艾滋病毒/艾滋病患者和免疫力低的人迁移到传播率高的地区，感染疟疾和患上严重疾病的风险更高。其中，5岁以下儿童占非洲所有疟疾死亡人数的80%。此外，疟疾对疟疾流行国家的经济产生负面影响，使儿童失学，成人失业或工作，助长贫穷循环，增加脆弱卫生系统的压力。在过去五年中，疟疾发病率和死亡率的下降停滞不前，东南亚和非洲对现行护理标准的抵制正在上升。迫切需要新的抗疟剂用于治疗和预防。我们的研究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合成酶对于疟疾寄生虫的生存至关重要。我们发现了两种干扰这种酶功能的分子，它们有可能被开发成治疗和预防疟疾感染的新药。然而，这两种分子不够有效，不具有口服药物所需的性质。我们选择这些分子之一MMV 019721进行优化。我们现在已经开发出更有效的分子，具有改进的特性，可以口服给药，我们有信心进一步优化疟疾新疗法的潜力。该提案的目的是改善这类分子的性质，以根据疟疾风险药物（MMV）晚期铅标准提供申报的晚期铅。这将需要我们优化分子的多个特征，包括其杀死疟疾寄生虫的能力，其到达寄生虫所在的身体部位而不被分解的能力以及其安全性。在项目结束时，后期的铅将准备进入更先进的毒理学研究，然后再进入人体临床试验。