Model Organisms in Drug Discovery

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REFERENCES 39 Uetz, P., Giot, L., Cagney, G., Mansfield, T. A., Judson, R. S., Knight, J. R., Lockshon, D., et al. (2000). A comprehensive analysis of protein–protein interactions in Saccharomyces cerevisiae [process citation]. Nature 403, 623–627. Uren, A. G., O’Rourke, K., Aravind, L. A., Pisabarro, M. T., Seshagiri, S., Koonin, E. V. and Dixit, V. M. (2000). Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma. Mol. Cell 6, 961–967. Wiederrecht, G., Brizuela, L., Elliston, K., Sigal, N. H. and Siekierka, J. J. (1991). FKB1 encodes a nonessential FK 506-binding protein in Saccharomyces cerevisiae and contains regions suggesting homology to the cyclophilins. Proc. Natl. Acad. Sci. USA 88, 1029– 1033. Wilson, W. A., Wang, Z. and Roach, P. J. (2002). Systematic identification of the genes affecting glycogen storage in the yeast Saccharomyces cerevisiae. Mol. Cell. Proteom. 1, 232–242. Winzeler, E. A., Shoemaker, D. D., Astromoff, A., Liang, H., Anderson, K., Andre, B., Bangham, R., et al. (1999). Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis. Science 285, 901–906. Wood, V., Gwilliam, R., Rajandream, M. A., Lyne, M., Lyne, R., Stewart, A., Sgouros, J., et al. (2002). The genome sequence of Schizosaccharomyces pombe. Nature 415, 871–880. Zhang, H., Cowan-Jacob, S. W., Simonen, M., Greenhalf, W., Heim, J. and Meyhack, B. (2000). Structural basis of BFL-1 for its interaction with BAX and its anti-apoptotic action in mammalian and yeast cells. J. Biol. Chem. 275, 11092–11099. Zhong, H. and Neubig, R. R. (2001). Regulator of G protein signaling proteins: novel multifunctional drug targets. J. Pharmacol. Exp. Ther. 297, 837–845. Zhu, H. and Snyder, M. (2002). ‘Omic’ approaches for unraveling signaling networks. Curr. Opin. Cell Biol. 14, 173–179. Zhu, H., Klemic, J. F., Chang, S., Bertone, P., Casamayor, A., Klemic, K. G., Smith, D., et al. (2000). Analysis of yeast protein kinases using protein chips. Nat. Genet. 26, 283–289. Zhu, H., Bilgin, M., Bangham, R., Hall, D., Casamayor, A., Bertone, P., Lan, N., Jansen, R., Bidlingmaier, S., Houfek, T., et al. (2001). Global analysis of protein activities using proteome chips. Science 293, 2101–2105.
3 Caenorhabditis elegans Functional Genomics in Drug Discovery: Expanding Paradigms Titus Kaletta, Lynn Butler and Thierry Bogaert In the past 10 years genomics has integrated rapidly into the process of drug discovery. Consequently, a wealth of novel targets need to be validated and screened to deliver more drugs in a shorter time. This asks for an animal model that is complex enough to acknowledge the complexity of modern medicine but also simple enough to be used in high-throughput applications. Caenorhabditis elegans is the ideal model organism and was identified by Sydney Brenner about 40 years ago. It is a spool-shaped worm ca. 1 mm long with 959 cells that eats bacteria. It is genetically amenable and transparent, so every cell division and differentiation could be followed directly under the microscope. Brenner demonstrated in 1974 that mutations could be introduced into many genes and visualized as distinct changes in organ formation. Through his visionary work Brenner created an important research tool: the nematode had made it into the inner circle of research and its utility for biomedical research has just been awarded a Nobel prize. This chapter describes C. elegans as a modern industrial tool for drug discovery. After an introduction into the drug discovery process and into C. elegans, various sections cover the design of C. elegans disease models, target identification technologies and genome-wide target validation approaches. Subsequent sections cover such topics as C. elegans compound assay design, C. elegans high-throughput screening and C. elegans pharmacology. The reader will be Model Organisms in Drug Discovery. Edited by Pamela M. Carroll and Kevin Fitzgerald Copyright © 2003 John Wiley & Sons, Ltd. ISBN: 0-470-84893-6
Page 1 and 2: Model Organisms in Drug Discovery M
Page 3 and 4: Copyright u 2003 John Wiley & Sons
Page 5 and 6: Contents List of contributors .....
Page 7 and 8: CONTENTS ix 7 Genetics and Genomics
Page 9 and 10: List of Contributors Hector Beltran
Page 11 and 12: LIST OF CONTRIBUTORS xiii Stefan Sc
Page 13 and 14: 1 Introduction to Model Systems in
Page 15 and 16: Organism INTEGRATING MODEL ORGANISM
Page 17 and 18: INTEGRATING MODEL ORGANISM RESEARCH
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Page 21 and 22: 10 GROWING YEAST FOR FUN AND PROFIT
Page 49: 38 GROWING YEAST FOR FUN AND PROFIT
Page 53 and 54: THE DRUG DISCOVERY PROCESS 43 thoug
Page 55 and 56: multivulva phenotype of Ras gain-of
Page 57 and 58: disease. These molecular targets ar
Page 59 and 60: FROM DISEASE TO TARGET 49 Figure 3.
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Page 63 and 64: signaling pathway. The third catego
Page 65 and 66: FROM DISEASE TO TARGET 55 resistant
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Page 69 and 70: profiles. The C. elegans gene expre
Page 71 and 72: emerging technologies. Forward gene
Page 73 and 74: The compound library LEAD DISCOVERY
Page 75 and 76: LEAD DISCOVERY 65 previous section,
Page 77 and 78: LEAD DISCOVERY 67 Figure 3.5 Distri
Page 79 and 80: Compound learning set for assay val
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Page 83 and 84: transporter itself. The SSRIs that
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Page 91 and 92: 82 DROSOPHILA AS A TOOL FOR DRUG DI
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92 DROSOPHILA AS A TOOL FOR DRUG DI
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100 DROSOPHILA AS A TOOL FOR DRUG D
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5 Drosophila - a Model System for T
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EVOLUTIONARY CONSERVATION OF DISEAS
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TARGET IDENTIFICATION/TARGET VALIDA
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CHEMICAL GENETICS 143 acid identity
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3. A hit identifies a biologically
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about their function in a multicell
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REFERENCES 149 Han, Z. S., Enslen,
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REFERENCES 151 Rintelen, F., Stocke
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6 Mechanism of Action in Model Orga
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INTRODUCTION TO COMPOUND DEVELOPMEN
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MODEL ORGANISMS ARRIVE ON THE SCENE
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ELUCIDATING THE MECHANISM OF COMPOU
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ELUCIDATING THE MECHANISM OF COMPOU
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A CASE STUDY FOR ALZHEIMER’S DISE
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NEW CHEMICAL GENETIC STRATEGIES 171
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A CASE STUDY FOR INNATE IMMUNITY 17
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GLOBAL GENE EXPRESSION STUDIES IN M
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As described above, the extensive i
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REFERENCES 179 Austin, J. and Kimbl
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REFERENCES 181 Hughes, T. R., Marto
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REFERENCES 183 Sin, N., Meng, L., W
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186 GENETICS AND GENOMICS IN THE ZE
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8 Lipid Metabolism and Signaling in
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FISH AS A MODEL ORGANISM 205 genes
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LIPID METABOLISM SCREEN 207 transpo
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LIPID METABOLISM SCREEN 209 Figure
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the embryo media containing radioac
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ZEBRAFISH AS A MODEL SYSTEM 213 Fig
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ZEBRAFISH AS A MODEL SYSTEM 215 Reg
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aspirin, which has potent inhibitor
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REFERENCES 219 Chau, I. and Cunning
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REFERENCES 221 Patrono, C., Patrign
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224 CHEMICAL MUTAGENESIS IN THE MOU
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252 SATURATION SCREENING OF DRUGGAB
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280 INDEX bupropion 92 busulfan 143
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282 INDEX Dscam 171 dual-energy X-r
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284 INDEX L-685,818 16 lead discove
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286 INDEX protein function 19-22 pr
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288 INDEX yeast (continued) functio
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