Chemical genetics: Ligand-based discovery of gene function

Nature Reviews Genetics

Volumn 1, Issue 2, 2000, Pages 116-125

  Stockwell, Brent R ^a  

^a WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

LIGAND; PEPTIDE LIBRARY; PROTEIN;

ANIMAL; DATA BASE; GENE; GENE LIBRARY; GENETICS; METHODOLOGY; MOLECULAR BIOLOGY; REVIEW;

ANIMALS; DATABASES; GENE LIBRARY; GENES; LIGANDS; MOLECULAR BIOLOGY; PEPTIDE LIBRARY; PROTEINS;

EID: 0034331004     PISSN: 14710056     EISSN: None     Source Type: Journal    
DOI: 10.1038/35038557     Document Type: Review

References (107)

1. Hartwell, L. H. Twenty-five years of cell cycle genetics. Genetics 4, 975-980 (1991).
2. Metzstein, M. M., Stanfield, G. M. & Horvitz, H. R. Genetics of programmed cell death in C. elegans: past, present and future. Trends Genet. 14, 410-416 (1998).
3. Nusslein-Volhard, C. & Wieschaus, E. Mutations affecting segment number and polarity in Drosophila. Nature 287, 795-801 (1980).
4. Justice, M. J., Noveroske, J. K., Weber, J. S., Zheng, B. & Bradley, A. Mouse ENU mutagenesis. Hum. Mol. Genet. 8, 1955-1963 (1999).
5. Mullins, M. C., Hammerschmidt, M., Haffter, P. & Nusslein-Volhard, C. Large-scale mutagenesis in the zebrafish: in search of genes controlling development in a vertebrate. Curr. Biol. 4, 189-201 (1994).
6. Vitaterna, M. H. et al. Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science 264, 719-725 (1994). This study was the first to successfully use random mutagenesis, phenotype-based screening and positional cloning (that is, a forward-genetic approach) in mice.
7. Reppert, S. M. & Weaver, D. R. Forward genetic approach strikes gold: cloning of a mammalian Clock gene. Cell 89, 487-490 (1997).
8. Munroe, R. J. et al. Mouse mutants from chemically mutagenized embryonic stem cells. Nature Genet. 24, 318-321 (2000).
9. Schena, M. et al. Parallel human genome analysis: microarray-based expression monitoring of 1000 genes. Proc. Natl Acad. Sci. USA 93, 10614-10619 (1996).
10. Schreiber, S. L. Chemical genetics resulting from a passion for synthetic organic chemistry. Bioorg. Med. Chem. 6, 1127-1152 (1998).
11. Stockwell, B. R., Haggarty, S. J. & Schreiber, S. L. High-throughput screening of small molecules in miniaturized mammalian cell-based assays involving post-translational modifications. Chem. Biol. 6, 71-83 (1999).
12. Agrawal, S. & Zhao, Q. Antisense therapeutics. Curr. Opin. Chem. Biol. 2, 519-528 (1998).
13. Dervan, P. B. & Burli, R. W. Sequence-specific DNA recognition by polyamides. Curr. Opin. Chem. Biol. 3, 688-693 (1999).
14. Parascandola, J. The theoretical basis of Paul Ehrlich's chemotherapy. J. Hist. Med. Allied Sci. 36, 19-43 (1981).
15. Schmitz, R. Friedrich Wilhelm Serturner and the discovery of morphine. Pharm. Hist. 27, 61-74 (1985).
16. Parascandola, J. Reflections on the history of pharmacology: the 1980 Kremers award address. Pharm. Hist. 22, 131-140 (1980).
17. Ehrlich, P. Chemotherapeutics: Scientific principles, methods and results. Lancet ii, 445-451 (1913).
18. Travis, A. S. Science as a receptor of technology: Paul Ehrlich and the synthetic dyestuffs industry. Sci. Context 3, 383-408 (1989).
19. Travis, A. S. Perkin's mauve: ancestor of the organic chemical industry. Technol. Cult. 31, 51-82 (1990).
20. Popescu, A. & Doyle, R. J. The Gram stain after more than a century. Biotech. Histochem. 71, 145-151 (1996).
21. McTavish, J. R. Aspirin in Germany: the pharmaceutical industry and the pharmaceutical profession. Pharm. Hist. 29, 103-115 (1987).
22. Kaufman, G. B. & Priebe, P. M. The discovery of saccharin: a centennial retrospect. Ambix 25, 191-207 (1978).
23. Geyer, C. R., Colman-Lerner, A. & Brent, R. 'Mutagenesis' by peptide aptamers identifies genetic network members and pathway connections. Proc. Natl Acad. Sci. USA 96, 8567-8572 (1999). This is the first successful use of peptide aptamers in a forward chemical-genetic screen.
24. Colas, P. Combinatorial protein reagents to manipulate protein function. Curr. Opin. Chem. Biol. 4, 54-59 (2000).
25. Dolle, R. E. Comprehensive survey of chemical libraries yielding enzyme inhibitors, receptor agonists and antagonists, and other biologically active agents: 1992 through 1997. Mol. Diversity 3, 199-233 (1998).
26. Dolle, R. E. & Nelson, K. H., Jr Comprehensive survey of combinatorial library synthesis: 1998. J. Comb. Chem. 1, 235-282 (1999).
27. Merrifield, B. Concept and early development of solid-phase peptide synthesis. Methods Enzymol. 289, 3-13 (1997).
28. Schneider, C. H., Rolli, H. & Blaser, K. Liquid-liquid extraction in peptide synthesis. Int. J. Pept. Protein Res. 15, 411-419 (1980).
29. Lam, K. S. et al. A new type of synthetic peptide library for identifying ligand-binding activity. Nature 354, 82-84 (1991).
30. Furka, A., Sebestyen, F., Asgedom, M. & Dido, G. General method for rapid synthesis of multicomponent peptide mixtures. Int. J. Pept. Protein Res. 37, 487-493 (1991). References 29 and 30 describe split-pool synthesis, a revolutionary method for synthesizing very large chemical libraries.
31. Fodor. S. P. et al. Light-directed, spatially addressable parallel chemical synthesis. Science 251, 767-773 (1991).
32. Scott, J. K. & Smith, G. P. Searching for peptide ligands with an epitope library. Science 249, 386-390 (1990).
33. Colas, P. et al. Genetic selection of peptide aptamers that recognize and inhibit cyclin-dependent kinase 2. Nature 380, 548-550 (1996).
34. Lien, E. J. & Wang, P. H. Upophilicity, molecular weight, and drug action: reexamination of parabolic and bilinear models. J. Pharmacol. Sci. 69, 648-650 (1980).
35. Tan, D. S., Foley, M. A., Stockwell, B. R., Shair, M. D. & Schreiber, S. L. Synthesis and preliminary evaluation of a library of polycyclic small molecules for use in chemical genetic assays. J. Am. Chem. Soc. 121, 9073-9087 (1999).
36. Sullivan, R. W. et al. 2-Chloro-4-(trifluoromethyl)pyrimidine-5-N-(3′,5′- bis(trifluoromethyl)phenyl)-carboxamide: a potent inhibitor of NF-κB- and AP-1-mediated gene expression identified using solution-phase combinatorial chemistry. J. Med. Chem. 41, 413-419 (1998).
37. An, H., Haly, B. D. & Cook, P. D. Discovery of novel pyridinopolyamines with potent antimicrobial activity: deconvolution of mixtures synthesized by solution-phase combinatorial chemistry. J. Med. Chem. 41, 706-716 (1998).
38. Boger, D. L. Chai, W. & Jin, Q. Multistep convergent solution-phase combinatorial synthesis and deletion synthesis deconvolution. J. Am. Chem. Soc. 120, 7220-7225 (1998).
39. Hung, D. T., Jamison, T. F. & Schreiber, S. L. Understanding and controlling the cell cycle with natural products. Chem. Biol. 3, 623-640 (1996).
40. Handelsman, J., Rondon, M. R., Brady, S. F., Clardy, J. & Goodman, R. M. Molecular biological access to the chemistry of unknown soil microbes: a new frontier for natural products. Chem. Biol. 5, 245-249 (1998). The authors describe a powerful method for discovering new natural products using bacterial genetics.
41. Tan, D. S., Foley, M. A., Shair, M. D. & Schreiber, S. L. Stereoselective synthesis of over two million compounds having structural features both reminiscent of natural products and compatible with miniaturized cell-based assays. J. Am. Chem. Soc. 120, 8565-8566 (1998). This is the first demonstrated use of combinatorial chemistry to synthesize a large library of structurally complex small molecules.
42. Wang, J. & Ramnarayan, K. Toward designing drug-like libraries: a novel computational approach for prediction of drug feasibility of compounds. J. Comb. Chem. 1, 524-533 (1999).
43. Gellman, S. H. Foldamers: a manifesto. Acc. Chem. Res. 31, 173-180 (1998).
44. Schreiber, S. L. Target-oriented and diversity-oriented organic synthesis in drug discovery. Science 287, 1964-1969 (2000).
45. Vaino, A. R. & Janda, K. D. Euclidean shape-encoded combinatorial chemical libraries. Proc. Natl Acad. Sci. USA 97, 7692-7696 (2000).
46. Sundberg, S. A. High-throughput and ultra-high-throughput screening: solution- and cell-based approaches. Curr. Opin. Biotechnol. 11, 47-53 (2000).
47. Borchardt, A., Liberles, S. D., Biggar, S. R., Crabtree, G. R. & Schreiber, S. L. Small molecule-dependent genetic selection in stochastic nanodroplets as a means of detecting protein-ligand interactions on a large scale. Chem. Biol. 4, 961-968 (1997).
48. You, A. J., Jackman, R. J., Whitesides, G. M. & Schreiber, S. L. A miniaturized arrayed assay format for detecting small molecule-protein interactions in cells. Chem. Biol. 4, 969-975 (1997).
49. Mere, L. et al. Miniaturized FRET assays and microfluidics: key components for ultra-high-throughput screening. Drug Discov. Today 4, 363-369 (1999).
50. Wetterau, J. R. et al. An MTP inhibitor that normalizes atherogenic lipoprotein levels in WHHL rabbits. Science 282, 751-754 (1998).
51. Komarov, P. G. et al. A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science 285, 1733-1737 (1999).
52. Sebolt-Leopold, J. S. et al. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nature Med. 5, 810-816 (1999).
53. Aramburu, J. et al. Affinity-driven peptide selection of an NFAT inhibitor more selective than cyclosporin A. Science 285, 2129-2133 (1999).
54. Apletalina, E., Appel, J., Lamango, N. S., Houghten, R. A. & Lindberg, I. Identification of inhibitors of prohormone convertases 1 and 2 using a peptide combinatorial library. J. Biol. Chem. 273, 26585-26595 (1998).
55. Tian, S. S. et al. A small, nonpeptidyl mimic of granulocyte-colony-stimulating factor. Science 281, 257-259 (1998).
56. Zhang, B. et al. Discovery of a small molecule insulin mimetic with antidiabetic activity in mice. Science 284, 974-977 (1999).
57. Chen, J. K., Lane, W. S., Brauer, A. W., Tanaka, A. & Schreiber, S. L. Biased combinatorial libraries: Novel ligands for the SH3 domain of phosphatidylinositol 3-kinase. J. Am. Chem. Soc. 115, 12591-12592 (1993).
58. Bottger, V. et al. Identification of novel mdm2 binding peptides by phage display. Oncogene 13, 2141-2147 (1996).
59. Norris, J. D. et al. Peptide antagonists of the human estrogen receptor. Science 285, 744-746 (1999).
60. Rohrer, S. P. et al. Rapid identification of subtype-selective agonists of the somatostatin receptor through combinatorial chemistry. Science 282, 737-740 (1998). These authors were the first to apply reverse chemical-genetics to a protein family. They identify specific small molecule partners of each member of a family of somatostatin cell-surface receptors.
61. Norman, T. C. et al. Genetic selection of peptide inhibitors of biological pathways. Science 285, 591-595 (1999).
62. Mayer, T. U. et al. Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 286, 971-974 (1999).
63. Rosania, G. R. et al. Myoseverin, a microtubule-binding molecule with novel cellular effects. Nature Biotechnol. 18, 304-308 (2000).
64. Hrabe de Angelis, M. H. et al. Genome-wide, large-scale production of mutant mice by ENU mutagenesis. Nature Genet. 25, 444-447 (2000).
65. Nolan, P. M. et al. A systematic, genome-wide, phenotype-driven mutagenesis programme for gene function studies in the mouse. Nature Genet. 25, 440-443 (2000).
66. Stockwell, B. R., Hardwick, J. S., Tong, J. K. & Schreiber, S. L. Chemical genetic and genomic approaches reveal a role for copper in specific gene activation. J. Am. Chem. Soc. 121, 10662-10663 (1999).
67. Boland, M. V., Markey, M. K. & Murphy, R. F. Automated recognition of patterns characteristic of subcellular structures in fluorescence microscopy images. Cytometry 33, 366-375 (1998).
68. Kino, T. et al. FK-506, a novel immunosuppressant isolated from a Streptomyces I. Fermentation, isolation, and physico-chemical and biological characteristics. J. Antibiot. (Tokyo) XL, 1249-1255 (1987).
69. Kino, T. et al. FK-506. A novel immunosupressant isolated from a Streptomyces II. Immunosuppressive effect of FK-506 in vitro. J. Antibiot. (Tokyo) XL, 1256-1265 (1987).
70. Haggarty, S. J. et al. Dissecting cellular processes using small molecules: identification of colchicine-like, taxol-like and other small molecules that perturb mitosis. Chem. Biol. 7, 275-286 (2000).
71. Roberge, M. et al. High-throughput assay for G2 checkpoint inhibitors and identification of the structurally novel compound isogranulatimide. Cancer Res. 58, 5701-5706 (1998).
72. Caponigro, G. et al. Transdominant genetic analysis of a growth control pathway. Proc. Natl Acad. Sci. USA 95, 7508-7513 (1998).
73. Yamaguchi, K. et al. 4-Phenylthiazole derivatives inhibit IL-6 secretion in osteoblastic cells and suppress bone weight loss in ovariectomized mice. Bioorg. Med. Chem. Lett. 9, 957-960 (1999).
74. Lu, X. P. et al. Novel retinoid-related molecules as apoptosis inducers and effective inhibitors of human lung cancer cells in vivo. Nature Med. 3, 686-690 (1997).
75. Rice, J. W., Davis, J. E., Crowl, R. M. & Johnston, P. A. Development of a high volume screen to identify inhibitors of endothelial cell activation. Anal. Biochem. 241, 254-259 (1996).
76. Goldstein, A. The interactions of drugs and plasma proteins. Pharmacol. Rev. 1, 102-163 (1949).
77. Karlin, A. & Winnik, M. Reduction and specific alkylation of the receptor for acetycholine. Proc. Natl Acad. Sci. USA 60, 668-674 (1968).
78. Raftery, M. A., Hunkapiller, M. W., Strader, C. D. & Hood, L. E. Acetylcholine receptor: complex of homologous subunits. Science 208, 1454-1457 (1980).
79. Noda, M. et al. Primary structure of α-subunit precursor of Torpedo californica acetylcholine receptor deduced from cDNA sequence. Nature 299, 793-797 (1982).
80. Kornel, L. On the effects and the mechanism of action of corticosteroids in normal and neoplastic target tissues: findings and hypotheses. Acta Endocrinol. Suppl. (Copenh.) 178, 1-45 (1973).
81. Liu, J. et al. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 66, 807-815 (1991).
82. Brown, E. J. et al. & Schreiber, S. L. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369, 756-758 (1994).
83. Taunton, J., Hassig, C. A. & Schreiber, S. L. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 272, 408-411 (1996). The authors demonstrate the power of affinity chromatography and biochemical purification to identify the protein target of the natural product trapoxin.
84. Sin, N. et al. The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase MetAP-2. Proc. Natl Acad. Sci. USA 94, 6099-6103 (1997).
85. Kwon, H. J., Owa, T., Hassig, C. A., Shimada, J. & Schreiber, S. L. Depudecin induces morphological reversion of transformed fibroblasts via the inhibition of histone deacetylase. Proc. Natl Acad. Sci. USA 95, 3356-3361 (1998).
86. Fenteany, G. et al. Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin. Science 268, 726-731 (1995).
87. Sche, P. P., McKenzie, K. M., White, J. D. & Austin, D. J. Display cloning: functional identification of natural product receptors using cDNA-phage display. Chem. Biol. 6, 707-716 (1999).
88. Hughes, T. R. et al. Functional discovery via a compendium of expression profiles. Cell 102, 109-126 (2000).
89. Giaever, G. et al. Genomic profiling of drug sensitivities via induced haploinsufficiency. Nature Genet. 21, 278-283 (1999).
90. Winzeler, E. A. et al. Direct allelic variation scanning of the yeast genome. Science 281, 1194-1197 (1998).
91. Colas, P. & Brent, R. The impact of two-hybrid and related methods on biotechnology. Trends Biotechnol. 16, 355-363 (1998).
92. Licitra, E. J. & Liu, J. O. A three-hybrid system for detecting small ligand-protein receptor interactions. Proc. Natl Acad. Sci. USA 93, 12817-12821 (1996).
93. Marton, M. J., et al. Drug target validation and identification of secondary drug target effects using DNA microarrays. Nature Med. 4, 1293-1301 (1998). The authors demonstrate the utility of expression profiling for identifying the target(s) of a small molecule.
94. Giroux, S. et al. Embryonic death of Mek1-deficient mice reveals a role for this kinase in angiogenesis in the labyrinthine region of the placenta. Curr. Biol. 9, 369-372 (1999).
95. Blum, J. H., Dove, S. L., Hochschild, A. & Mekalanos, J. J. Isolation of peptide aptamers that inhibit intracellular processes. Proc. Natl Acad. Sci. USA 97, 2241-2246 (2000).
96. Adey, N. B. & Kay, B. K. Identification of calmodulin-binding peptide consensus sequences from a phage-displayed random peptide library. Gene 169, 133-134 (1996).
97. Wrighton, N. C. et al. Small peptides as potent mimetics of the protein hormone erythropoietin. Science 273, 458-463 (1996).
98. Wrighton, N. C., Barrett, R. W. & Dower, W. J. Peptide agonist of the thrombopoietin receptor as potent as the natural cytokine. Science 276, 1696-1699 (1997).
99. Yayon, A. et al. Isolation of peptides that inhibit binding of basic fibroblast growth factor to its receptor from a random phage-epitope library. Proc. Natl Acad. Sci. USA 90, 10643-10647 (1993).
100. Yanofsky, S. D. et al. High affinity type I interleukin 1 receptor antagonists discovered by screening recombinant peptide libraries. Proc. Natl Acad Sci. USA 93, 7381-7386 (1996).
101. Maly, D. J., Choong, I. C. & Ellman, J. A. Combinatorial target-guided ligand assembly: identification of potent subtype-selective c-Src inhibitors. Proc. Natl Acad. Sci. USA 97, 2419-2924 (2000).
102. Richter, L. S. & Moos, W. H. Discovery of nanomolar ligands for 7-transmembrane G-protein-coupled receptors from a diverse N-(substituted)glycine peptoid library. J. Med. Chem. 37, 2678-2685 (1994).
103. Liang, R. et al. Parallel synthesis and screening of a solid phase carbohydrate library. Science 274, 1520-1522 (1996).
104. Szardenings, A. K. et al. Identification of highly selective inhibitors of collagenase-1 from combinatorial libraries of diketopiperazines. J. Med. Chem. 42, 1348-1357 (1999).
105. Bunin, B. A. & Ellman, J. A. A general and expedient method for the solid phase synthesis of 1,4-benzodiazepine derivatives. J. Am. Chem. Soc. 114, 10997-10998 (1992).
106. Peisach, E. et al. Interaction of a peptidomimetic aminimide inhibitor with elastase. Science 269, 66-69 (1995).
107. Bailey, N. et al. A convenient procedure for the solution phase preparation of 2-aminothiazole combinatorial libraries. Bioorg. Med. Chem. Lett. 6, 1409-1414 (1996).