DMPK Optimisation of B-hydroxyethylamine Antimalarials

疟疾是由疟原虫传播的一个严重的世界性公共卫生问题，仅在2020年就造成约62.7万人死亡，对目前治疗方法的抗药性突显出需要具有新的作用机制的新疗法。理想情况下，成功的候选药物将在疟疾的三个生命周期阶段(肝脏、血液和蚊子)表现出多阶段的活性。纤溶酶原蛋白(PM)是疟疾寄生虫用于各种功能的天冬氨酸蛋白酶，PMIX和PMX是很好的药物靶标，因为它们共同参与了所有三个生命周期阶段。它们对寄生虫的外泄和入侵是必不可少的，而PMIX/X抑制剂具有独特的作用机制，因此耐药性发展的障碍很高。早期的铅系列B-羟乙胺在体外和体内都有优异的抗疟疾效力，因为它们模仿PMIX/PMX及其蛋白底物形成的过渡态。然而，它们受到较差的DMPK图谱的限制，因此该项目的一个关键目标是优化DMPK的特性--特别是代谢稳定性，同时还设计出增加细胞膜通透性的方法。将筛选类似物的体外靶标酶抑制、表型抗疟疾评估和PK测试。此外，该项目还将审查光亲和探针的合成，以便在生物活性评估后启动化学蛋白质组靶向参与研究。

Malaria is a severe, worldwide public health problem spread by Plasmodium parasites which caused an estimated 627,000 deaths in 2020 alone, and resistance to current treatment highlights the need for newer therapeutics with novel mechanisms of action. Successful drug candidates would ideally show multistage activity on the three life cycle stages (liver, blood, and mosquito) of malaria. Plasmepsins (PMs) are aspartic acid proteases used by malaria parasites for various functions, and PMIX and PMX make excellent drug targets as they together are involved in all three life cycle stages. They are essential for parasite egress and invasion, and PMIX/X inhibitors have a unique mechanism of action, therefore the barrier to resistance development is high. An early lead series of B-hydroxyethylamines have reported exceptional antimalarial potency in vitro and in vivo, as they mimic the transition state formed by PMIX/PMX and their protein substrate. They are however limited by a poor DMPK profile, so a key aim of this project is to optimise the DMPK properties - particularly the metabolic stability but also devising approaches to increase cell membrane permeability. Analogues will be screened for in vitro target enzyme inhibition, phenotypic antimalarial assessment, and PK testing. In addition, this project will also examine the synthesis of photoaffinity probes to enable chemical proteomic target engagement studies to be initiated post biological activity assessment.