Identification of β-hematin inhibitors in a high-throughput screening effort reveals scaffolds with in vitro antimalarial activity.
Identification of β-hematin inhibitors in a high-throughput screening effort reveals scaffolds with in vitro antimalarial activity.
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DOI：
10.1016/j.ijpddr.2014.08.002
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发表时间：
2014-12
影响因子：
4
通讯作者：
Wright, David W.
中科院分区：
文献类型：
--
作者：
Sandlin, Rebecca D.;Fong, Kim Y.;Wicht, Kathryn J.;Carrell, Holly M.;Egan, Timothy J.;Wright, David W.
血球蛋白的形成是探索新先导化合物的主要药物靶向途径。我们研究了体外抑制β-血红素的VICB化合物文库。对两株恶性疟原虫进行了β-血红素抑制剂的体外抗疟活性试验。确定了具有靶向性和体外抗疟疾活性的化学支架。恶性疟原虫耐药株的出现。为开发新的抗疟疾药物创造了迫切的需求。血球蛋白的形成是一个重要的药物靶点，这是一种对寄生虫生存至关重要的结晶血红素解毒过程。喹啉类抗疟药包括氯喹和阿莫地喹，它们的抗疟疾活性归因于抑制血吸虫蛋白的形成。虽然在体内血球蛋白的形成是在中性脂存在的情况下发生的，但亲脂性洗涤剂NP-40先前被证明在β-血球蛋白(合成血球蛋白)的形成过程中起到替代作用。因此，建立了一种NP-40介导的β-血红素形成试验，用于高通量筛选。在这里，该方法被用于筛选144,330个化合物以鉴定结晶抑制物，结果是530次点击。为了确定这些靶向β-血红素抑制剂对恶性疟原虫的有效性，每一次打击都在寄生红细胞的培养中进行了进一步测试。这项工作表明，171种β-血红素抑制剂对寄生虫也有活性。剂量-反应数据表明，73种β-血红素抑制剂对⩽M的IC50值为5，其中包括25种具有抗恶性疟原虫纳摩尔活性的化合物。对这一数据的基于脚手架的分析确定了14个主要脚手架，占530个总点击量的46%。进一步评估了来自每个类别的代表性化合物在恶性疟原虫感染的人红细胞中的血球蛋白抑制活性。测试的每一种受试化合物都被发现是阳性抑制剂，而阴性对照在培养中不会干扰这一生物途径。
Hemozoin formation is a prime drug target pathway to probe for new lead compounds. We examined the VICB library of compounds for in vitro β-hematin inhibition. β-Hematin inhibitors were tested for in vitro antimalarial activity in two P. falciparum strains. Chemical scaffolds with target-specific and in vitro antimalarial activity were identified. The emergence of drug resistant strains of Plasmodium spp. creates a critical need for the development of novel antimalarials. Formation of hemozoin, a crystalline heme detoxification process vital to parasite survival serves as an important drug target. The quinoline antimalarials including chloroquine and amodiaquine owe their antimalarial activity to inhibition of hemozoin formation. Though in vivo formation of hemozoin occurs within the presence of neutral lipids, the lipophilic detergent NP-40 was previously shown to serve as a surrogate in the β-hematin (synthetic hemozoin) formation process. Consequently, an NP-40 mediated β-hematin formation assay was developed for use in high-throughput screening. Here, the assay was utilized to screen 144,330 compounds for the identification of inhibitors of crystallization, resulting in 530 hits. To establish the effectiveness of these target-based β-hematin inhibitors against Plasmodiumfalciparum, each hit was further tested in cultures of parasitized red blood cells. This effort revealed that 171 of the β-hematin inhibitors are also active against the parasite. Dose–response data identified 73 of these β-hematin inhibitors have IC50 values ⩽5 μM, including 25 compounds with nanomolar activity against P. falciparum. A scaffold-based analysis of this data identified 14 primary scaffolds that represent 46% of the 530 total hits. Representative compounds from each of the classes were further assessed for hemozoin inhibitory activity in P. falciparum infected human erythrocytes. Each of the hit compounds tested were found to be positive inhibitors, while a negative control did not perturb this biological pathway in culture.
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影响因子：
3
作者：
Ambele MA;Egan TJ
通讯作者：
Egan TJ
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.1118120109
发表时间：
2012-07-10
影响因子：
11.1
作者：
Kapishnikov, Sergey;Weiner, Allon;Elbaum, Michael
通讯作者：
Elbaum, Michael
影响因子：
56.9
作者：
Martin, Rowena E.;Marchetti, Rosa V.;Kirk, Kiaran
通讯作者：
Kirk, Kiaran