Fast acting allosteric phosphofructokinase inhibitors block trypanosome glycolysis and cure acute African trypanosomiasis in mice.
Fast acting allosteric phosphofructokinase inhibitors block trypanosome glycolysis and cure acute African trypanosomiasis in mice.
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速效变构磷酸果糖激酶抑制剂阻断锥虫糖酵解并治愈小鼠急性非洲锥虫病。
DOI：
10.1038/s41467-021-21273-6
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发表时间：
2021-02-16
影响因子：
16.6
通讯作者：
Walkinshaw MD
中科院分区：
文献类型：
--
作者：
McNae IW;Kinkead J;Malik D;Yen LH;Walker MK;Swain C;Webster SP;Gray N;Fernandes PM;Myburgh E;Blackburn EA;Ritchie R;Austin C;Wear MA;Highton AJ;Keats AJ;Vong A;Dornan J;Mottram JC;Michels PAM;Pettit S;Walkinshaw MD
寄生原生体布鲁氏锥虫是非洲人类锥虫病（又称昏睡病）的病原体。这种寄生虫通过采采蝇的叮咬进入血液，它完全依靠糖酵解来产生ATP。糖酵解酶由于其高度保守的活性位点和磷酸化的底物而被认为是具有挑战性的药物靶点。我们描述了新型小分子变甾抑制剂的发展锥虫磷酸果糖激酶（PFK）阻断糖酵解途径，导致非常快的寄生虫杀死时间，而不抑制人类PFK。这些化合物穿过血脑屏障，一天口服剂量可治愈非洲人类锥虫病1期动物模型中的寄生虫血症。这项研究表明，靶向糖酵解是可能的，并且还显示了变张机制的差异如何允许开发物种特异性抑制剂来解决一系列增殖性或感染性疾病。糖酵解酶由于其高度保守的活性位点和磷酸化底物而成为具有挑战性的药物靶点。本研究中，作者鉴定了布鲁氏锥虫磷酸果糖激酶的速效变构抑制剂，阻断了锥虫糖酵解，并在小鼠模型中提供了治愈的证据。
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. Glycolytic enzymes are challenging drug targets due to their highly conserved active sites and phosphorylated substrates. Here, the authors identify fast acting allosteric inhibitors of Trypanosoma brucei phosphofructokinase that block trypanosome glycolysis and provide cure evidence in murine model.
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影响因子：
3.8
作者：
McLatchie, Alex P.;Burrell-Saward, Hollie;Taylor, Martin C.
通讯作者：
Taylor, Martin C.
影响因子：
3.8
作者：
Myburgh E;Coles JA;Ritchie R;Kennedy PG;McLatchie AP;Rodgers J;Taylor MC;Barrett MP;Brewer JM;Mottram JC
通讯作者：
Mottram JC
影响因子：
3.5
作者：
Nowicki, Matthew W.;Tulloch, Lindsay B.;Turner, Nicholas J.
通讯作者：
Turner, Nicholas J.
影响因子：
4.2
作者：
Brimacombe, Kyle R.;Walsh, Martin J.;Boxer, Matthew B.
通讯作者：
Boxer, Matthew B.
影响因子：
5.6
作者：
McNae, Iain W.;Martinez-Oyanedel, Jose;Walkinshaw, Malcolm D.
通讯作者：
Walkinshaw, Malcolm D.