Fumagillin and Fumarranol Interact with P. falciparum Methionine Aminopeptidase 2 and Inhibit Malaria Parasite Growth In Vitro and In Vivo
Fumagillin and Fumarranol Interact with P. falciparum Methionine Aminopeptidase 2 and Inhibit Malaria Parasite Growth In Vitro and In Vivo
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DOI：
10.1016/j.chembiol.2009.01.006
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发表时间：
2009-02-27
影响因子：
--
通讯作者：
Liu, Jun O.
中科院分区：
文献类型：
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作者：
Chen, Xiaochun;Xie, Suji;Liu, Jun O.
已知烟曲霉素家族的天然产物通过不可逆地抑制人2型甲硫氨酸氨基肽酶（MetAP 2）来抑制血管生成。最近，据报道，烟曲霉素和TNP-470在体外具有抗疟疾活性，并且假设这种抑制是通过与人MetAP 2的假定疟疾直系同源物的相互作用介导的。在这份报告中，我们从细菌、酵母和昆虫细胞中过表达并纯化了近同质的PfMetAP 2。虽然在现有的测定中没有PfMetAP 2的重组形式表现出酶活性，但在酵母和昆虫细胞中表达的PfMetAP 2蛋白能够在下拉测定中结合烟曲霉素。烟曲霉素和类似物与PfMetAP 2之间的相互作用使用新建立的哺乳动物三杂交测定进一步证明，该测定掺入地塞米松和烟曲霉素之间的缀合物。与人（Hs）MetAP 2不同，发现PfMetAP 2与烟曲霉素非共价结合。重要的是，一种新的烟曲霉素类似物，曲马诺，被证明与PfMetAP 2相互作用，并抑制氯喹敏感和耐药恶性疟原虫菌株在体外的生长。还使用小鼠疟疾模型在体内证明了烟曲霉素和藜芦醇的抗寄生虫活性。这些研究结果表明，PfMetAP 2是一个可行的目标，和藜芦醇是一个有前途的先导化合物，用于开发新的抗疟药。
The fumagillin family of natural products is known to inhibit angiogenesis through irreversible inhibition of human type 2 methionine aminopeptidase (MetAP2). Recently, fumagillin and TNP-470 were reported to possess antimalarial activity in vitro, and it was hypothesized that this inhibition was mediated by interaction with the putative malarial ortholog of human MetAP2. In this report, we have overexpressed and purified to near-homogeneity PfMetAP2 from bacteria, yeast, and insect cells. Although none of the recombinant forms of PfMetAP2 exhibited enzymatic activity in existing assays, PfMetAP2 proteins expressed in both yeast and insect cells were able to bind to fumagillin in a pull-down assay. The interaction between fumagillin and analogs with PfMetAP2 was further demonstrated using a newly established mammalian three-hybrid assay incorporating a conjugate between dexamethasone and fumagillin. Unlike human (Hs)MetAP2, it was found that PfMetAP2 is bound to fumagillin noncovalently. Importantly, a new analog of fumagillin, fumarranol, was demonstrated to interact with PfMetAP2 and inhibit the growth of both chloroquine-sensitive and drug-resistant Plasmodium falciparum strains in vitro. Antiparasite activity of fumagillin and fumarranol was also demonstrated in vivo using a mouse malaria model. These findings suggest that PfMetAP2 is a viable target, and fumarranol is a promising lead compound for the development of novel antimalarial agents.