A yeast-based screen reveals that sulfasalazine inhibits tetrahydrobiopterin biosynthesis
A yeast-based screen reveals that sulfasalazine inhibits tetrahydrobiopterin biosynthesis
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DOI：
10.1038/nchembio.557
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发表时间：
2011-06-01
影响因子：
14.8
通讯作者：
Johnsson, Kai
中科院分区：
文献类型：
--
作者：
Chidley, Christopher;Haruki, Hirohito;Johnsson, Kai
我们介绍了一种检测药物-蛋白质相互作用的方法，该方法结合了一种新的酵母三杂交筛选，用于鉴定相互作用，并通过亲和色谱进行明确的验证。我们将该方法应用于临床批准药物的分析，从而鉴定出先前已知和未知的药物-蛋白质相互作用。特别是，我们能够确定厄洛替尼和阿托伐他汀的脱靶点，以及抗肿瘤药物柳氮磺胺吡啶的酶靶点。我们证明，柳氮磺胺吡啶及其代谢产物，磺胺吡啶和美沙拉嗪，是酶的抑制剂催化的最后一步的辅因子四氢生物蝶呤的生物合成。对四氢生物蝶呤代谢的干扰为柳氮磺胺吡啶的一些有益和有害特性提供了解释，并进一步表明了该药物的新的和改进的疗法。因此，这项工作建立了一个强大的药物分析方法，并提供了新的见解，在临床批准的药物的作用机制。
We introduce an approach for detection of drug-protein interactions that combines a new yeast three-hybrid screening for identification of interactions with affinity chromatography for their unambiguous validation. We applied the methodology to the profiling of clinically approved drugs, resulting in the identification of previously known and unknown drug-protein interactions. In particular, we were able to identify off-targets for erlotinib and atorvastatin, as well as an enzyme target for the antiinflammatory drug sulfasalazine. We demonstrate that sulfasalazine and its metabolites, sulfapyridine and mesalamine, are inhibitors of the enzyme catalyzing the final step in the biosynthesis of the cofactor tetrahydrobiopterin. The interference with tetrahydrobiopterin metabolism provides an explanation for some of the beneficial and deleterious properties of sulfasalazine and furthermore suggests new and improved therapies for the drug. This work thus establishes a powerful approach for drug profiling and provides new insights in the mechanism of action of clinically approved drugs.