Current Proteomics, 2005, 2, 1-13 1 1570-1646/05 $50.00+.00 ©2005 Bentham Science Publishers Ltd. Drug Discovery Using Yeast as a Model System: A Functional Genomic and Proteomic View Daniel Auerbach 1 , Anthony Arnoldo 2 , Boris Bogdan 2 , Michael Fetchko 2 and Igor Stagljar 2, * 1 Dualsystems Biotech Inc., Winterthurerstrasse 190, CH-8057 Zurich, Switzerland and 2 Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich-Irchel, Winterthurerstrasse, 190, CH-8057 Zurich, Switzerland Abstract: Drug discovery is a complex process that includes the identification of biological targets as well as the identification of leads that aim at altering or inhibiting the function of a particular target. The budding yeast Saccharomyces cerevisiae has long been recognized as a valuable model organism for studies of eukaryotic cells since many of the basic cellular processes between yeast and humans are highly conserved. In this review, we highlight emerging yeast-based functional genomic and proteomic technologies that are advancing the utility of yeast as a model organism in the drug-discovery process. These approaches include the utilization of yeast deletion strain collection, synthetic genetic array combined with chemical genomics, variations of the yeast two-hybrid system, yeast biosensor assay, and protein microarrays. Although still at an early stage, these technologies show promise as novel and useful methods for development of target-specific therapeutic approaches. Key Words: Drug discovery, yeast two hybrid system, genomics, proteomics. INTRODUCTION Drug discovery is a lengthy and costly process which involves target identification and validation, drug screening and safety assays, development of animal models and ultimately, testing of potential drug candidates in clinical trials. The development of a novel drug may take 10-15 years, with cost estimates of ~800 million US$ (DiMasi et al., 2003). Any technology that is able to increase the speed of the screening process and deliver more reliable predic- tions on the efficacy or potential toxicity of drug candidates, and thereby effectively help to cut cost and time in this process, would be helpful. Both genomics and proteomics have been considered to be effective for such purpose. Whereas genomics can speed up the target identification process by making complete genome sequences of a wide range of organisms available (http://www.genomenews network.org/resources/sequenced _ genomes / genome _ guide _ p1.shtml), proteomics holds the promise of identifying the complete set of proteins expressed in a particular cell at a given stage, as well as uncovering the myriad of regulatory networks that are created by protein-protein interactions. Ultimately, using systems biology one should be able to receive a “snap-shot” of a cell with all information regarding expressed proteins, their particular localization within the cell, their post-translational modification status and their interactions with various other proteins expressed at the same time. To date, the major impact of proteomics has been on processes in the early stages of drug development, namely target identification and validation. In particular, the use of *Address correspondence to this author at the Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich-Irchel, Winterthurerstrasse, 190, CH-8057 Zurich, Switzerland; Tel: +41-1-635 54 74; Fax: +41-1-635 68 40; Email: stagljar@vetbio.unizh.ch model organisms such as the bakers yeast Saccharomyces cerevisiae, the fruit fly Drosophila melanogaster and the worm Caenorhabditis elegans has been very helpful since many human genes have orthologues in lower eukaryotes (consortium, 2001; Venter et al., 2001). In this review, we focus on the use of the model organism S. cerevisiae and its applications in finding and characterizing disease pathways, as well as on attempts at converting yeast to an in vivo screening platform to identify novel compounds in the early stage of drug development. These include the use of engineered yeast strains in assessing the toxicity of drug candidates, synthetic genetic array combined with chemical genomics, the establishment of large scale protein interac- tions maps from several organisms and attempts to use these maps to predict pathways implicated with human diseases, the direct use of yeast two-hybrid strategies to identify novel drug candidates that alter or inhibit protein-protein interac- tions, and the application of protein microarrays for drug discovery. The reader is referred to several excellent recent reviews covering additional yeast based functional genomics technologies that are not covered here (Hughes, 2002; Melese and Hieter, 2002; Parsons et al., 2004; Tucker, 2002). YEAST AS A MODEL SYSTEM FOR DRUG DISCOVERY The unicellular eukaryote S. cerevisiae is an excellent model system for drug discovery: it is inexpensive to maintain and grow, it is classified as a GRAS (generally recognized as safe) microorganism, its entire genome has been sequenced (Goffeau et al., 1996), its ~ 6, 200 open reading frames (ORFs) exist in a readily usable form (Hudson et al ., 1997), it is well suited for the expression of heterologous proteins, and it contains a multitude of selective markers, including markers for nutritional selection (e.g. HIS3, URA3) , drug resistance (e.g. kanMX, patMX,