Validation of the Proteasome as a Therapeutic Target in Plasmodium Using an Epoxyketone Inhibitor with Parasite-Specific Toxicity
Validation of the Proteasome as a Therapeutic Target in Plasmodium Using an Epoxyketone Inhibitor with Parasite-Specific Toxicity
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DOI：
10.1016/j.chembiol.2012.09.019
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发表时间：
2012-12-21
影响因子：
--
通讯作者：
Bogyo, Matthew
中科院分区：
文献类型：
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作者：
Li, Hao;Ponder, Elizabeth L.;Bogyo, Matthew
疟原虫蛋白酶体已被认为是一个潜在的抗疟药物的目标，然而，抑制剂的毒性阻止了这种酶在体内的验证。我们报告了最近美国食品和药物管理局批准的抑制剂卡非佐米的670个类似物的库的筛选，以确定选择性杀死寄生虫的化合物。我们鉴定了一种化合物PR3，其在体外具有显著的寄生虫杀灭活性，但在宿主细胞中的毒性显著降低。我们发现，这种寄生虫特异性毒性不是由于疟原虫蛋白酶体对宿主蛋白酶体的选择性靶向，而是由于缺乏对人类蛋白酶体亚基之一的活性。随后，我们使用PR3显着降低伯氏疟原虫感染小鼠的寄生虫负荷，而没有宿主毒性，从而验证蛋白酶体作为一个可行的抗疟药物靶标。
The Plasmodium proteasome has been suggested to be a potential antimalarial drug target; however, toxicity of inhibitors has prevented validation of this enzyme in vivo. We report a screen of a library of 670 analogs of the recent US Food and Drug Administration-approved inhibitor, carfilzomib, to identify compounds that selectively kill parasites. We identified one compound, PR3, that has significant parasite killing activity in vitro but dramatically reduced toxicity in host cells. We found that this parasite-specific toxicity is not due to selective targeting of the Plasmodium proteasome over the host proteasome, but instead is due to a lack of activity against one of the human proteasome subunits. Subsequently, we used PR3 to significantly reduce parasite load in Plasmodium berghei infected mice without host toxicity, thus validating the proteasome as a viable antimalarial drug target.