DXR Inhibition by Potent Mono- and Disubstituted Fosmidomycin Analogues
DXR Inhibition by Potent Mono- and Disubstituted Fosmidomycin Analogues
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DOI：
10.1021/jm4006498
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发表时间：
2013-08-08
影响因子：
7.3
通讯作者：
Mowbray, Sherry L.
中科院分区：
文献类型：
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作者：
Jansson, Anna M.;Wieckowska, Anna;Mowbray, Sherry L.
抗疟化合物磷咪霉素靶向DXR，DXR是催化MEP途径中第一个关键步骤的酶，产生必需的类异戊二烯前体异戊烯基二磷酸和二甲基烯丙基二磷酸。MEP途径被许多病原体使用，包括结核分枝杆菌和顶复门寄生虫，并且不同于人类必需的经典甲羟戊酸途径。使用基于结构的方法，我们设计了一些类似物的磷霉素，包括一系列的取代在C α和羟肟酸的位置。后者被证明是一个稳定的框架，用于设计从极性和狭窄（因此不容易药物化）的底物结合位点延伸的抑制剂，并可以首次桥接底物和辅因子结合位点。在体外试验中，这些化合物中的许多在杀死恶性疟原虫方面比磷霉素更有效;最好的IC 50为40 nM。
The antimalarial compound fosmidomycin targets DXR, the enzyme that catalyzes the first committed step in the MEP pathway, producing the essential isoprenoid precursors, isopentenyl diphosphate and dimethylallyl diphosphate. The MEP pathway is used by a number of pathogens, including Mycobacterium tuberculosis and apicomplexan parasites, and differs from the classical mevalonate pathway that is essential in humans. Using a structure-based approach, we designed a number of analogues of fosmidomycin, including a series that are substituted in both the C alpha and the hydroxamate positions. The latter proved to be a stable framework for the design of inhibitors that extend from the polar and cramped (and so not easily druggable) substrate-binding site and can, for the first time, bridge the substrate and cofactor binding sites. A number of these compounds are more potent than fosmidomycin in terms of killing Plasmodium falciparum in an in vitro assay; the best has an IC50 of 40 nM.