Identification of β-hematin inhibitors in the MMV Malaria Box.
Identification of β-hematin inhibitors in the MMV Malaria Box.
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DOI：
10.1016/j.ijpddr.2015.05.003
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发表时间：
2015-12
影响因子：
4
通讯作者：
Wright, David W.
中科院分区：
文献类型：
--
作者：
Fong, Kim Y.;Sandlin, Rebecca D.;Wright, David W.
Malaria Box 由 Medicines for Malaria Venture 组装，由 400 种结构多样的市售化合物组成，已证明具有对抗血液阶段恶性疟原虫的活性。这些化合物是圣裘德儿童研究医院（美国田纳西州）、诺华公司和葛兰素史克公司通过高通量筛选工作鉴定出的 20,000 种体外抗疟药的代表性子集。此外，来自商业库的一小组活性化合物也被添加到该组中，但之前尚未发表。阐明这些化合物作用的生化途径是一项重大挑战；因此，研究人员可以免费获取这些化合物。在这里，测试了 Malaria Box 化合物对抗 β-血红素形成的活性，β-血红素是血红素解毒生物矿物质、疟原虫色素的合成形式。此外，还探索了这些化合物在疟疾寄生虫中的作用机制。 Malaria Box 的 10 种化合物显示出对 β-血红素形成的显着抑制作用。在此测定中，剂量反应数据显示这些命中的 IC50 值范围为 8.7 至 22.7 μM，其中每一个都比氯喹（一种已知的疟原虫色素形成抑制剂）更有效。这十种命中的体外抗疟活性在氯喹敏感的 D6 寄生虫菌株培养物中得到证实，导致 IC50 值为 135–2165 nM，随后在多重耐药菌株 C235 中进行测试。然后，在用九种市售已确认化合物处理后，检查恶性疟原虫 (D6) 培养物的血红素分布，其中七种化合物破坏了疟原虫色素途径。 400 种 Malaria Box 化合物中有 10 种被发现是有效的 β-血红素抑制剂。我们确认了与之前筛选结果相似的体外抗疟活性。 9 种市售热门产品中有 7 种是在培养物中经过验证的疟原虫色素抑制剂。
The Malaria Box, assembled by the Medicines for Malaria Venture, is a set of 400 structurally diverse, commercially available compounds with demonstrated activity against blood-stage Plasmodium falciparum. The compounds are a representative subset of the 20,000 in vitro antimalarials identified from the high-throughput screening efforts of St. Jude Children's Research Hospital (TN, USA), Novartis and GlaxoSmithKline. In addition, a small set of active compounds from commercially available libraries was added to this group, but it has not previously been published. Elucidation of the biochemical pathways on which these compounds act is a major challenge; therefore, access to these compounds has been made available free of charge to the investigator community. Here, the Malaria Box compounds were tested for activity against the formation of β-hematin, a synthetic form of the heme detoxification biomineral, hemozoin. Further, the mechanism of action of these compounds within the malaria parasite was explored. Ten of the Malaria Box compounds demonstrated significant inhibition of β-hematin formation. In this assay, dose–response data revealed IC50 values ranging from 8.7 to 22.7 μM for these hits, each of which is more potent than chloroquine (a known inhibitor of hemozoin formation). The in vitro antimalarial activity of these ten hits was confirmed in cultures of the chloroquine sensitive D6 strain of the parasite resulting in IC50 values of 135–2165 nM, followed by testing in the multidrug resistant strain, C235. Cultures of P. falciparum (D6) were then examined for their heme distribution following treatment with nine of the commercially available confirmed compounds, seven of which disrupted the hemozoin pathway. Ten of 400 Malaria Box compounds were found to be potent β-hematin inhibitors. We confirmed similar in vitro antimalarial activity to results from previous screens. 7 of the 9 commercially available hits were validated hemozoin inhibitors in culture.
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影响因子：
15.8
作者：
Delves M;Plouffe D;Scheurer C;Meister S;Wittlin S;Winzeler EA;Sinden RE;Leroy D
通讯作者：
Leroy D
影响因子：
2.9
作者：
Ncokazi, KK;Egan, TJ
通讯作者：
Egan, TJ
DOI：
10.1039/b914359a
发表时间：
2010-02-07
期刊：
Dalton transactions (Cambridge, England : 2003)
影响因子：
--
作者：
Hoang AN;Ncokazi KK;de Villiers KA;Wright DW;Egan TJ
通讯作者：
Egan TJ
DOI：
10.1073/pnas.0802982105
发表时间：
2008-07-01
影响因子：
11.1
作者：
Plouffe, David;Brinker, Achim;Winzeler, Elizabeth A.
通讯作者：
Winzeler, Elizabeth A.
影响因子：
64.8
作者：
Gamo, Francisco-Javier;Sanz, Laura M.;Garcia-Bustos, Jose F.
通讯作者：
Garcia-Bustos, Jose F.