Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum.
Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum.
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DOI：
10.1016/j.bmc.2009.01.024
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发表时间：
2009-02-15
影响因子：
3.5
通讯作者：
Brodsky, Jeffrey L.
中科院分区：
文献类型：
--
作者：
Chiang, Annette N.;Valderramos, Juan-Carlos;Balachandran, Raghavan;Chovatiya, Raj J.;Mead, Brian P.;Schneider, Corinne;Bell, Samantha L.;Klein, Michael G.;Huryn, Donna M.;Chen, Xiaojiang S.;Day, Billy W.;Fidock, David A.;Wipf, Peter;Brodsky, Jeffrey L.
恶性疟原虫是导致最致命形式的人类疟疾的顶复体寄生虫，在其复杂的生命周期中暴露于完全不同的环境和压力因素。在任何生物体中，Hsp70伴侣通常与对压力的耐受性有关。因此，我们认为抑制恶性疟原虫Hsp70伴侣会对寄生虫的稳态产生不利影响。为了验证这一假设，我们测量了嘧啶-酰胺（一类新的Hsp70调节剂）是否可以抑制人类红细胞中致病性恶性疟原虫阶段的复制。共鉴定出9个IC50值在30 nM ~ 1.6 μM范围内的化合物。在单次转化试验中，每种化合物也改变了纯化恶性疟原虫Hsp70的atp酶活性，尽管需要比抑制恶性疟原虫复制所需的浓度更高的试剂。这些化合物对来自其他生物体的热休克蛋白70的不同影响也被观察到。总之，我们的数据表明，嘧啶酰胺构成了一类新的抗疟疾药物。
Plasmodium falciparum, the Apicomplexan parasite that is responsible for the most lethal forms of human malaria, is exposed to radically different environments and stress factors during its complex lifecycle. In any organism, Hsp70 chaperones are typically associated with tolerance to stress. We therefore reasoned that inhibition of P. falciparum Hsp70 chaperones would adversely affect parasite homeostasis. To test this hypothesis, we measured whether pyrimidinone-amides, a new class of Hsp70 modulators, could inhibit the replication of the pathogenic P. falciparum stages in human red blood cells. Nine compounds with IC50 values from 30 nM to 1.6 μM were identified. Each compound also altered the ATPase activity of purified P. falciparum Hsp70 in single-turnover assays, although higher concentrations of agents were required than was necessary to inhibit P. falciparum replication. Varying effects of these compounds on Hsp70s from other organisms were also observed. Together, our data indicate that pyrimidinone-amides constitute a novel class of anti-malarial agents.
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影响因子：
2.9
作者：
NADEAU, K;NADLER, SG;WALSH, CT
通讯作者：
WALSH, CT
影响因子：
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Shonhai, A;Boshoff, A;Blatch, GL
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影响因子：
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通讯作者：
Cowman AF
影响因子：
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作者：
Mayer, MP;Bukau, B
通讯作者：
Bukau, B