Howieson Vanessa M, Tran Elisa, Hoegl Annabelle, Fam Han Ling, Fu Jonathan, Sivonen Kate, Li Xiao Xuan, Auclair Karine, Saliba Kevin J
Research School of Biology, The Australian National University, Canberra, ACT, Australia.
Department of Chemistry, McGill University, Montreal, Canada.
Antimicrob Agents Chemother. 2016 Nov 21;60(12):7146-7152. doi: 10.1128/AAC.01436-16. Print 2016 Dec.
The biosynthesis of coenzyme A (CoA) from pantothenate and the utilization of CoA in essential biochemical pathways represent promising antimalarial drug targets. Pantothenamides, amide derivatives of pantothenate, have potential as antimalarials, but a serum enzyme called pantetheinase degrades pantothenamides, rendering them inactive in vivo In this study, we characterize a series of 19 compounds that mimic pantothenamides with a stable triazole group instead of the labile amide. Two of these pantothenamides are active against the intraerythrocytic stage parasite with 50% inhibitory concentrations (ICs) of ∼50 nM, and three others have submicromolar ICs. We show that the compounds target CoA biosynthesis and/or utilization. We investigated one of the compounds for its ability to interact with the Plasmodium falciparum pantothenate kinase, the first enzyme involved in the conversion of pantothenate to CoA, and show that the compound inhibits the phosphorylation of [C]pantothenate by the P. falciparum pantothenate kinase, but the inhibition does not correlate with antiplasmodial activity. Furthermore, the compounds are not toxic to human cells and, importantly, are not degraded by pantetheinase.
从泛酸盐生物合成辅酶A（CoA）以及CoA在重要生化途径中的利用是很有前景的抗疟药物靶点。泛酰硫乙胺，泛酸盐的酰胺衍生物，具有作为抗疟药的潜力，但一种名为泛肽酶的血清酶会降解泛酰硫乙胺，使其在体内失去活性。在本研究中，我们对一系列19种化合物进行了表征，这些化合物模拟泛酰硫乙胺，带有稳定的三唑基团而非易降解的酰胺。其中两种泛酰硫乙胺对红细胞内期寄生虫具有活性，50%抑制浓度（IC50）约为50 nM，另外三种的IC50为亚微摩尔级别。我们表明这些化合物靶向CoA的生物合成和/或利用。我们研究了其中一种化合物与恶性疟原虫泛酸盐激酶相互作用的能力，泛酸盐激酶是参与泛酸盐转化为CoA的首个酶，结果表明该化合物抑制恶性疟原虫泛酸盐激酶对[C]泛酸盐的磷酸化，但这种抑制作用与抗疟活性无关。此外，这些化合物对人类细胞无毒，重要的是，它们不会被泛肽酶降解。
