Vivas Livia, Easton Anna, Kendrick Howard, Cameron Angus, Lavandera Jose-Luis, Barros David, de las Heras Federico Gomez, Brady R Leo, Croft Simon L
Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK.
Exp Parasitol. 2005 Oct;111(2):105-14. doi: 10.1016/j.exppara.2005.06.007.
Plasmodium falciparum lactate dehydrogenase (PfLDH) is essential for ATP generation. Based on structural differences within the active site between P. falciparum and human LDH, we have identified a series of heterocyclic azole-based inhibitors that selectively bind within the PfLDH but not the human LDH (hLDH) active site and showed anti-malarial activity in vitro and in vivo. Here we expand on an azole, OXD1, from this series and found that the anti-P. falciparum activity was retained against a panel of strains independently of their anti-malarial drug sensitivity profile. Trophozoites had relatively higher PfLDH enzyme activity and PfLDH-RNA expression levels than rings and were the most susceptible stages to OXD1 exposure. This is probably linked to their increased energy requirements and consistent with glycolysis being an essential metabolic pathway for parasite survival within the erythrocyte. Further structural elaboration of these azoles could lead to the identification of compounds that target P. falciparum through such a novel mechanism and with more potent anti-malarial activity.
恶性疟原虫乳酸脱氢酶（PfLDH）对于ATP的生成至关重要。基于恶性疟原虫与人类乳酸脱氢酶活性位点的结构差异，我们鉴定出了一系列基于杂环唑的抑制剂，它们能选择性地结合在PfLDH而非人类乳酸脱氢酶（hLDH）的活性位点内，并在体外和体内均表现出抗疟活性。在此，我们对该系列中的一种唑类化合物OXD1进行拓展研究，发现其对一组疟原虫菌株均保留了抗恶性疟原虫活性，且与它们的抗疟药物敏感性谱无关。滋养体的PfLDH酶活性和PfLDH-RNA表达水平相对高于环状体，并且是对OXD1暴露最敏感的阶段。这可能与它们增加的能量需求有关，并且与糖酵解作为疟原虫在红细胞内生存的必需代谢途径相一致。对这些唑类化合物进行进一步的结构优化，可能会鉴定出通过这种新机制靶向恶性疟原虫且具有更强抗疟活性的化合物。
