Wellcome Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Michael Swann Building, Max Born Crescent, Edinburgh, UK.
Selcia Ltd., Fyfield Business and Research Park, Fyfield Road, Ongar, Essex, UK.
Nat Commun. 2021 Feb 16;12(1):1052. doi: 10.1038/s41467-021-21273-6.
The parasitic protist Trypanosoma brucei is the causative agent of Human African Trypanosomiasis, also known as sleeping sickness. The parasite enters the blood via the bite of the tsetse fly where it is wholly reliant on glycolysis for the production of ATP. Glycolytic enzymes have been regarded as challenging drug targets because of their highly conserved active sites and phosphorylated substrates. We describe the development of novel small molecule allosteric inhibitors of trypanosome phosphofructokinase (PFK) that block the glycolytic pathway resulting in very fast parasite kill times with no inhibition of human PFKs. The compounds cross the blood brain barrier and single day oral dosing cures parasitaemia in a stage 1 animal model of human African trypanosomiasis. This study demonstrates that it is possible to target glycolysis and additionally shows how differences in allosteric mechanisms may allow the development of species-specific inhibitors to tackle a range of proliferative or infectious diseases.
寄生原生动物布氏锥虫是引起人类非洲锥虫病(又称昏睡病)的病原体。寄生虫通过采采蝇的叮咬进入血液,在那里它完全依赖糖酵解来产生 ATP。糖酵解酶一直被认为是具有挑战性的药物靶点,因为它们的高度保守的活性位点和磷酸化底物。我们描述了新型小分子别构抑制剂的开发锥虫磷酸果糖激酶(PFK),阻断糖酵解途径,导致非常快速的寄生虫杀伤时间,而对人 PFKs 没有抑制作用。这些化合物可以穿过血脑屏障,在人类非洲锥虫病的 1 期动物模型中,每天口服一次可治愈寄生虫血症。本研究表明,靶向糖酵解是可能的,此外还表明,变构机制的差异如何允许开发针对特定物种的抑制剂来解决一系列增殖或传染性疾病。