off-target effects of psychoactive drugs revealed by genome-wide assays in yeast精神药物的脱靶效应揭示了在酵母全基因组分析.pdfVIP

Off-Target Effects of Psychoactive Drugs Revealed by Genome-Wide Assays in Yeast 1,2 1,2 1,2 3 2,3,4 Elke Ericson , Marinella Gebbia , Lawrence E. Heisler , Jan Wildenhain , Mike Tyers , Guri Giaever1,2, Corey Nislow2,5* 1 Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada, 2 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada, 3 School of Biological Sciences, The University of Edinburgh, Edinburgh, United Kingdom, 4 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, 5 Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario, Canada Abstract To better understand off-target effects of widely prescribed psychoactive drugs, we performed a comprehensive series of chemogenomic screens using the budding yeast Saccharomyces cerevisiae as a model system. Because the known human targets of these drugs do not exist in yeast, we could employ the yeast gene deletion collections and parallel fitness profiling to explore potential off-target effects in a genome-wide manner. Among 214 tested, documented psychoactive drugs, we identified 81 compounds that inhibited wild-type yeast growth and were thus selected for genome-wide fitness profiling. Many of these drugs had a propensity to affect multiple cellular functions. The sensitivity profiles of half of the analyzed drugs were enriched for core cellular processes such as secretion, protein folding, RNA processing, and chromatin structure. Interestingly, fluoxetine (Prozac) interfered with establishment of cell polarity, cyproheptadine (Periactin) targeted essential genes with chromatin-remodeling roles, while paroxetine (Paxil) in