Repurposing drugs to target the malaria parasite unfolding protein response.
Repurposing drugs to target the malaria parasite unfolding protein response.
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DOI：
10.1038/s41598-018-28608-2
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发表时间：
2018-07-09
影响因子：
4.6
通讯作者：
Pizarro JC
中科院分区：
文献类型：
--
作者：
Chen Y;Murillo-Solano C;Kirkpatrick MG;Antoshchenko T;Park HW;Pizarro JC
抗药性恶性疟原虫寄生虫是我们控制疟疾这一致命病媒传染病的努力中的一个主要障碍。这种情况迫切需要找到和验证新的药物靶点，以遏制疾病的传播。与未折叠蛋白反应（UPR）相关的几个基因，包括葡萄糖调节蛋白78 kDa（GRP78，也称为BiP），已被认为是潜在的药物靶点。我们探索了GRP78的药物靶点潜力，GRP78是一种分子伴侣，是UPR的调节剂，用于治疗恶性疟原虫感染。通过筛选作为抗癌剂的再利用的伴侣蛋白抑制剂，我们表明GRP78抑制在体外对药物敏感的和耐药的恶性疟原虫寄生虫株是致命的。我们将抑制剂的抗疟原虫活性与其结合疟疾伴侣蛋白的能力相关联，通过表征其与重组寄生虫GRP78的结合。此外，我们用ADP确定了恶性疟原虫GRP78的ATP结合结构域的晶体结构，并鉴定了该寄生虫特有的结构特征。这些数据表明恶性疟原虫GRP78可以是有效的药物靶标，并且其与人GRP78的结构差异强调了产生寄生虫特异性化合物的潜力。
Drug resistant Plasmodium falciparum parasites represent a major obstacle in our efforts to control malaria, a deadly vector borne infectious disease. This situation creates an urgent need to find and validate new drug targets to contain the spread of the disease. Several genes associated with the unfolded protein response (UPR) including Glucose-regulated Protein 78 kDa (GRP78, also known as BiP) have been deemed potential drug targets. We explored the drug target potential of GRP78, a molecular chaperone that is a regulator of the UPR, for the treatment of P. falciparum parasite infection. By screening repurposed chaperone inhibitors that are anticancer agents, we showed that GRP78 inhibition is lethal to drug-sensitive and -resistant P. falciparum parasite strains in vitro. We correlated the antiplasmodial activity of the inhibitors with their ability to bind the malaria chaperone, by characterizing their binding to recombinant parasite GRP78. Furthermore, we determined the crystal structure of the ATP binding domain of P. falciparum GRP78 with ADP and identified structural features unique to the parasite. These data suggest that P. falciparum GRP78 can be a valid drug target and that its structural differences to human GRP78 emphasize potential to generate parasite specific compounds.
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影响因子：
7.3
作者：
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