Identification of inhibitors for putative malaria drug targets among novel antimalarial compounds
Identification of inhibitors for putative malaria drug targets among novel antimalarial compounds
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DOI：
10.1016/j.molbiopara.2010.08.005
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发表时间：
2011-01-01
影响因子：
1.5
通讯作者：
Kuhen, Kelli L.
中科院分区：
文献类型：
--
作者：
Crowther, Gregory J.;Napuli, Alberto J.;Kuhen, Kelli L.
大多数市售抗疟药物的疗效因寄生虫抗药性的演变而受到影响，这突出表明迫切需要找到具有新作用机制的新药。我们已经采取了一种高通量的方法来确定新的抗疟化学抑制剂的优先药物靶点恶性疟原虫，不包括目前使用的药物抑制的目标。对商业上可获得的文库的筛选鉴定出5655种低分子量化合物，其抑制恶性疟原虫培养物的生长，EC 50值低于1.25 μ M。然后在384孔或1536孔生物化学测定中测试这些化合物对九种疟原虫酶的活性：腺苷酸琥珀酸合成酶（AdSS）、胆碱激酶（CK）、脱氧尿苷三磷酸核苷酸水解酶（dUTR）、谷氨酸脱氢酶（GDH）、鸟苷酸激酶（GK）、N-肉豆蔻酰转移酶（NMT）、乳清酸苷5’-单磷酸脱羧酶（OMPDC）、法尼基焦磷酸合酶（FPPS）和S-腺苷高半胱氨酸水解酶（SAHH）。这些酶是使用TDRtargets.org选择的，并且基于诸如它们可能的必要性、药物稳定性和对高通量生化筛选的顺从性的标准，被认为具有作为药物靶标的优异潜力。其中6个靶点被一种或多种抗疟支架抑制，可能在药物开发、进一步的靶点验证研究以及恶性疟原虫生物化学和生物学的探索中具有潜在的用途。(C)2010爱思唯尔有限公司版权所有。
The efficacy of most marketed antimalarial drugs has been compromised by evolution of parasite resistance, underscoring an urgent need to find new drugs with new mechanisms of action. We have taken a high-throughput approach toward identifying novel antimalarial chemical inhibitors of prioritized drug targets for Plasmodium falciparum, excluding targets which are inhibited by currently used drugs. A screen of commercially available libraries identified 5655 low molecular weight compounds that inhibit growth of P. falciparum cultures with EC50 values below 1.25 mu M. These compounds were then tested in 384- or 1536-well biochemical assays for activity against nine Plasmodium enzymes: adenylosuccinate synthetase (AdSS), choline kinase (CK), deoxyuridine triphosphate nucleotidohydrolase (dUTPase), glutamate dehydrogenase (GDH), guanylate kinase (GK), N-myristoyltransferase (NMT), orotidine 5'-monophosphate decarboxylase (OMPDC), farnesyl pyrophosphate synthase (FPPS) and S-adenosylhomocysteine hydrolase (SAHH). These enzymes were selected using TDRtargets.org, and are believed to have excellent potential as drug targets based on criteria such as their likely essentiality, drug-gability, and amenability to high-throughput biochemical screening. Six of these targets were inhibited by one or more of the antimalarial scaffolds and may have potential use in drug development, further target validation studies and exploration of P. falciparum biochemistry and biology. (C) 2010 Elsevier B.V. All rights reserved.