Integration of chemical-genetic and genetic interaction data links bioactive compounds to cellular target pathways
Integration of chemical-genetic and genetic interaction data links bioactive compounds to cellular target pathways
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DOI：
10.1038/nbt919
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发表时间：
2004-01-01
影响因子：
46.9
通讯作者：
Boone, C
中科院分区：
文献类型：
--
作者：
Parsons, AB;Brost, RL;Boone, C
生物活性化合物是有价值的研究工具和药物先导，但往往难以确定其作用机制或细胞靶点。在这里，我们研究了整合化学-遗传和遗传相互作用数据的潜力，以揭示有关抑制化合物的途径和目标的信息。利用现有的酵母单倍体缺失突变体，我们生成了12种化合物的药物超敏（化学-遗传）谱。除了一组化合物特异性相互作用外，化学-遗传谱还确定了多药耐药所需的一大组基因。特别是，缺乏功能性空泡H+- atp酶的酵母菌突变体表现出多药敏感性，这一现象可能在哺乳动物细胞中保守。通过筛选多药耐药基因的化学-遗传谱，然后将化合物特异性谱与大规模遗传相互作用谱纲要聚类，我们能够识别目标途径或蛋白质。因此，该方法为推断作用机制提供了有力的手段。
Bioactive compounds can be valuable research tools and drug leads, but it is often difficult to identify their mechanism of action or cellular target. Here we investigate the potential for integration of chemical-genetic and genetic interaction data to reveal information about the pathways and targets of inhibitory compounds. Taking advantage of the existing complete set of yeast haploid deletion mutants, we generated drug-hypersensitivity (chemical-genetic) profiles for 12 compounds. In addition to a set of compound-specific interactions, the chemical-genetic profiles identified a large group of genes required for multidrug resistance. In particular, yeast mutants lacking a functional vacuolar H+-ATPase show multidrug sensitivity, a phenomenon that may be conserved in mammalian cells. By filtering chemical-genetic profiles for the multidrug-resistant genes and then clustering the compound-specific profiles with a compendium of large-scale genetic interaction profiles, we were able to identify target pathways or proteins. This method thus provides a powerful means for inferring mechanism of action.