Off-Target Effects of Psychoactive Drugs Revealed by Genome-Wide Assays in Yeast

Ericson, Elke; Gebbia, Marinella; Heisler, Lawrence E.; Wildenhain, Jan; Tyers, Mike; Giaever, Guri; Nislow, Corey

doi:10.1371/journal.pgen.1000151

Cited by 81 publications

(90 citation statements)

References 49 publications

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“…Haploinsufficiency screens have been used to identify essential protein targets of smallmolecule drugs and are much more stringent than synthetic-lethal screens. Response to sertraline has already been assessed using these knockout libraries, though in those experiments pools of deletions mutants were assayed in bulk as opposed to individually in separate wells (Ericson et al 2008).…”

Section: Swa2mentioning

confidence: 99%

“…The more recent study showed that deletion of genes involved in vesicle trafficking-a number of which have mammalian homologs-causes hypersensitivity to chlorpromazine. A similar gene set enriched in processes involved in the intracellular vesicle transport system was found to modulate sensitivity to a diverse collection of psychoactive drugs by a group using an unbiased chemical-genomic approach (Ericson et al 2008).In an effort to understand why sertraline exhibits cytotoxic effects in a model system lacking the putative protein target, we began by combining the unparalleled specificity of a drug-resistance selection with rapid and cost-effective microarray-enabled polymorphism detection. In other words, we used whole-genome tiling microarrays, as opposed to cloning by complementation, to locate rapidly resistance-conferring mutations.…”

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The Antidepressant Sertraline Targets Intracellular Vesiculogenic Membranes in Yeast

et al. 2010

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Numerous studies have shown that the clinical antidepressant sertraline (Zoloft) is biologically active in model systems, including fungi, which do not express its putative protein target, the serotonin/5-HT transporter, thus demonstrating the existence of one or more secondary targets. Here we show that in the absence of its putative protein target, sertraline targets phospholipid membranes that comprise the acidic organelles of the intracellular vesicle transport system by a mechanism consistent with the bilayer couple hypothesis. On the basis of a combination of drug-resistance selection and chemical-genomic screening, we hypothesize that loss of vacuolar ATPase activity reduces uptake of sertraline into cells, whereas dysregulation of clathrin function reduces the affinity of membranes for sertraline. Remarkably, sublethal doses of sertraline stimulate growth of mutants with impaired clathrin function. Ultrastructural studies of sertraline-treated cells revealed a phenotype that resembles phospholipidosis induced by cationic amphiphilic drugs in mammalian cells. Using reconstituted enzyme assays, we also demonstrated that sertraline inhibits phospholipase A 1 and phospholipase D, exhibits mixed effects on phospholipase C, and activates phospholipase A 2 . Overall, our study identifies two evolutionarily conserved membrane-active processes-vacuolar acidification and clathrin-coat formation-as modulators of sertraline's action at membranes. S ERTRALINE, whose trade name is Zoloft, is a Food and Drug Administration (FDA) approved drug that belongs to the pharmacological class of antidepressants called selective serotonin reuptake inhibitors (SSRIs) (Koe et al. 1983). The putative therapeutic target of SSRIs is the human serotonin/5-HT transporter (hSERT/5-HTT/SLC6A4), an integral membrane protein that mediates sodium-dependent reuptake of the monoamine neurotransmitter serotonin at presynaptic nerve terminals in the brain (Tatsumi et al. 1997;Mortensen et al. 2001;Meyer et al. 2004). Indeed, the recent crystal structure of sertraline bound to a bacterial leucine transporter, LeuT-a homolog of mammalian monoamine transporters-has led to the proposal of a corresponding high-affinity binding site for sertraline in hSERT (Zhou et al. 2009). Inhibition of hSERT-dependent reuptake by sertraline is thought to underlie its antidepressant effect in people, as documented extensively over the last two decades in the clinical psychiatric literature (reviewed in Cipriani et al. 2009).However, there are numerous examples of sertraline's effects on cellular physiology, including, most curiously, cytotoxicity in yeast (Lass-Flö rl et al. 2001a,b), by an unknown mechanism that does not involve hSERT, suggesting the existence of one or more heretofore unrecognized secondary drug targets that may be evolutionarily conserved (Levkovitz et al. 2007;Reddy et al. 2008). Those observations, coupled with reports that antidepressants can accumulate in the brains of people to concentrations at which ''off-target'' effects are see...

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Section: Swa2mentioning

confidence: 99%

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The Antidepressant Sertraline Targets Intracellular Vesiculogenic Membranes in Yeast

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“…Chemical-genetic profiling, whereby growth of the pooled deletion collection is scored for hypersensitivity to a compound, enables the identification of target and off-target pathways. This approach has been used to interrogate the mechanism of action of both novel and clinically approved drugs, including chemotherapeutics and neuroleptics (Lum et al, 2004;Parsons et al, 2004;Parsons et al, 2006;Ericson et al, 2008;Hillenmeyer et al, 2008). Compounds with similar chemicalgenetic profiles can be grouped to reveal similar modes of action and similar targets (Parsons et al, 2006;Hillenmeyer et al, 2008).…”

Section: Dmmbiologistsorg 640mentioning

confidence: 99%

Combined zebrafish-yeast chemical-genetic screens reveal gene–copper-nutrition interactions that modulate melanocyte pigmentation

Ishizaki

Spitzer

Wildenhain

et al. 2010

Disease Models &Amp; Mechanisms

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SUMMARY Hypopigmentation is a feature of copper deficiency in humans, as caused by mutation of the copper (Cu2+) transporter ATP7A in Menkes disease, or an inability to absorb copper after gastric surgery. However, many causes of copper deficiency are unknown, and genetic polymorphisms might underlie sensitivity to suboptimal environmental copper conditions. Here, we combined phenotypic screens in zebrafish for compounds that affect copper metabolism with yeast chemical-genetic profiles to identify pathways that are sensitive to copper depletion. Yeast chemical-genetic interactions revealed that defects in intracellular trafficking pathways cause sensitivity to low-copper conditions; partial knockdown of the analogous Ap3s1 and Ap1s1 trafficking components in zebrafish sensitized developing melanocytes to hypopigmentation in low-copper environmental conditions. Because trafficking pathways are essential for copper loading into cuproproteins, our results suggest that hypomorphic alleles of trafficking components might underlie sensitivity to reduced-copper nutrient conditions. In addition, we used zebrafish-yeast screening to identify a novel target pathway in copper metabolism for the small-molecule MEK kinase inhibitor U0126. The zebrafish-yeast screening method combines the power of zebrafish as a disease model with facile genome-scale identification of chemical-genetic interactions in yeast to enable the discovery and dissection of complex multigenic interactions in disease-gene networks.

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“…In some disease etiologies, targeting multiple proteins may improve the therapeutic efficacy, such as for antipsychotic drugs or kinase inhibitors with anticancer activity (1). However, off-target activity can lead to adverse drug reactions (ADR) such as the case with fenfluramine and torcetrapib, 2 agents halted in development because of fatal hypertension that was the consequence of secondary target inhibition (1)(2)(3). Highlighting the promiscuity of small molecule inhibitors, a recent in silico screening of 213 Roche compounds revealed an average of 6.3 target proteins per compound (1).…”

Section: Introductionmentioning

confidence: 99%

Nonproteasomal Targets of the Proteasome Inhibitors Bortezomib and Carfilzomib: a Link to Clinical Adverse Events

Arastu‐Kapur

Anderl

Kraus

et al. 2011

Clinical Cancer Research

363

303

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Purpose: Bortezomib (Velcade), a dipeptide boronate 20S proteasome inhibitor and an approved treatment option for multiple myeloma, is associated with a treatment-emergent, painful peripheral neuropathy (PN) in more than 30% of patients. Carfilzomib, a tetrapeptide epoxyketone proteasome inhibitor, currently in clinical investigation in myeloma, is associated with low rates of PN. We sought to determine whether PN represents a target-mediated adverse drug reaction (ADR).Experimental Design: Neurodegenerative effects of proteasome inhibitors were assessed in an in vitro model utilizing a differentiated neuronal cell line. Secondary targets of both inhibitors were identified by a multifaceted approach involving candidate screening, profiling with an activity-based probe, and database mining. Secondary target activity was measured in rats and patients receiving both inhibitors.Results: Despite equivalent levels of proteasome inhibition, only bortezomib reduced neurite length, suggesting a nonproteasomal mechanism. In cell lysates, bortezomib, but not carfilzomib, significantly inhibited the serine proteases cathepsin G (CatG), cathepsin A, chymase, dipeptidyl peptidase II, and HtrA2/Omi at potencies near or equivalent to that for the proteasome. Inhibition of CatG was detected in splenocytes of rats receiving bortezomib and in peripheral blood mononuclear cells derived from bortezomib-treated patients. Levels of HtrA2/Omi, which is known to be involved in neuronal survival, were upregulated in neuronal cells exposed to both proteasome inhibitors but was inhibited only by bortezomib exposure.Conclusion: These data show that bortezomib-induced neurodegeneration in vitro occurs via a proteasome-independent mechanism and that bortezomib inhibits several nonproteasomal targets in vitro and in vivo, which may play a role in its clinical ADR profile. Clin Cancer Res; 17(9); 2734-43. Ó2011 AACR.

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Off-Target Effects of Psychoactive Drugs Revealed by Genome-Wide Assays in Yeast

Cited by 81 publications

References 49 publications

The Antidepressant Sertraline Targets Intracellular Vesiculogenic Membranes in Yeast

The Antidepressant Sertraline Targets Intracellular Vesiculogenic Membranes in Yeast

Combined zebrafish-yeast chemical-genetic screens reveal gene–copper-nutrition interactions that modulate melanocyte pigmentation

Nonproteasomal Targets of the Proteasome Inhibitors Bortezomib and Carfilzomib: a Link to Clinical Adverse Events

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