Development of a Photo-Cross-Linkable Diaminoquinazoline Inhibitor for Target Identification in Plasmodium falciparum.,ACS Infectious Diseases

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Development of a Photo-Cross-Linkable Diaminoquinazoline Inhibitor for Target Identification in Plasmodium falciparum.
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2018-02-05 , DOI: 10.1021/acsinfecdis.7b00228
Alexandra S Lubin , Ainoa Rueda-Zubiaurre , Holly Matthews , Hella Baumann , Fabio R Fisher , Julia Morales-Sanfrutos , Kate S Hadavizadeh , Flore Nardella _{1,

2,

3} , Edward W Tate , Jake Baum , Artur Scherf _{1,

2,

3} , Matthew J Fuchter

Affiliation

Diaminoquinazolines represent a privileged scaffold for antimalarial discovery, including use as putative Plasmodium histone lysine methyltransferase inhibitors. Despite this, robust evidence for their molecular targets is lacking. Here we report the design and development of a small-molecule photo-cross-linkable probe to investigate the targets of our diaminoquinazoline series. We demonstrate the effectiveness of our designed probe for photoaffinity labeling of Plasmodium lysates and identify similarities between the target profiles of the probe and the representative diaminoquinazoline BIX-01294. Initial pull-down proteomics experiments identified 104 proteins from different classes, many of which are essential, highlighting the suitability of the developed probe as a valuable tool for target identification in Plasmodium falciparum.

中文翻译：

用于恶性疟原虫中靶标鉴定的光交联二氨基喹唑啉抑制剂的开发。

二氨基喹唑啉代表抗疟疾发现的特权支架，包括用作假定的疟原虫组蛋白赖氨酸甲基转移酶抑制剂。尽管如此，仍缺乏关于其分子靶标的有力证据。在这里，我们报告一种小分子光可交联探针的设计和开发，以研究我们的二氨基喹唑啉系列的目标。我们展示了我们设计的探针对疟原虫裂解物的光亲和标记的有效性，并鉴定了该探针的目标谱与代表性的二氨基喹唑啉BIX-01294之间的相似性。最初的下拉蛋白质组学实验鉴定了104种来自不同类别的蛋白质，其中许多蛋白质都是必不可少的，突出了开发的探针作为恶性疟原虫靶标鉴定的有价值工具的适用性。

更新日期：2018-01-29

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