کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1175550 961806 2009 7 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Drug–target identification from total cellular lysate by drug-induced conformational changes
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آنالیزی یا شیمی تجزیه
پیش نمایش صفحه اول مقاله
Drug–target identification from total cellular lysate by drug-induced conformational changes
چکیده انگلیسی

Identification of drug targets is a key step in the development of novel pharmaceuticals. To this end, chemical probes or affinity matrices are often used, requiring substantial structure–activity relationship (SAR) studies. Here we report on the development of a novel technique for drug–target identification from total cellular lysate conducted independently of SAR information. This technique relies on binding of a drug to its target inducing a conformational change in target protein, thereby altering its susceptibility to proteolysis and resulting in specific degradation in some cases or in protection of target protein in others. As proof of concept, three drugs with identified targets were used. First, incubation of cellular lysates with okadaic acid elicited a specific protective effect on its target, protein phosphatase 2A catalytic subunit. Second, specific protection from exogenous protease of FKBP12 by FK506 and Hsp90 fragments by radicicol were observed. We then used the method to validate the targets of UCS15A, an Src signaling inhibitor. UCS15A induced proteolysis of a number of proteins, one of which was identified as Sam68. These studies suggest that the technology may be generally useful for identification and validation of drug targets.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Analytical Biochemistry - Volume 385, Issue 2, 15 February 2009, Pages 314–320
نویسندگان
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