Interrogating a Hexokinase-Selected Small-Molecule Library for Inhibitors of Plasmodium falciparum Hexokinase
Interrogating a Hexokinase-Selected Small-Molecule Library for Inhibitors of Plasmodium falciparum Hexokinase
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DOI：
10.1128/aac.00662-13
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发表时间：
2013-08-01
影响因子：
4.9
通讯作者：
Morris, James C.
中科院分区：
文献类型：
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作者：
Harris, Michael T.;Walker, Dawn M.;Morris, James C.
疟原虫属的寄生虫在世界热带和亚热带地区引发疾病。恶性疟原虫（P. falciparum）是该寄生虫中最致命的种类之一，当它寄生于哺乳动物红细胞内时，依靠糖酵解来产生三磷酸腺苷（ATP）。糖酵解的第一步由己糖激酶（HK）催化。虽然55.3千道尔顿的恶性疟原虫己糖激酶（PfHK）与哺乳动物的己糖激酶有一些生化特性相同，包括受其产物抑制，但它与人的己糖激酶的氨基酸同一性有限（约26%），这表明可以研发针对该酶的特异性治疗药物。为此，对一个选定的己糖激酶抑制剂小分子库进行筛选，已确定了一类恶性疟原虫己糖激酶抑制剂，即异苯并噻唑啉酮类，其中一些的半数抑制浓度（IC₅₀）为0.6以及……
Parasites in the genus Plasmodium cause disease throughout the tropic and subtropical regions of the world. P. falciparum, one of the deadliest species of the parasite, relies on glycolysis for the generation of ATP while it inhabits the mammalian red blood cell. The first step in glycolysis is catalyzed by hexokinase (HK). While the 55.3-kDa P. falciparum HK (PfHK) shares several biochemical characteristics with mammalian HKs, including being inhibited by its products, it has limited amino acid identity (similar to 26%) to the human HKs, suggesting that enzyme-specific therapeutics could be generated. To that end, interrogation of a selected small-molecule library of HK inhibitors has identified a class of PfHK inhibitors, isobenzothiazolinones, some of which have 50% inhibitory concentrations (IC(50)s) of = 0.6 and