Associate editor: P.K. ChiangModel systems in drug discovery: chemical genetics meets genomics
Introduction
Drug discovery has evolved over the years mostly due to the development of new technologies combined with a less simplistic view and better understanding of biology. Drugs were once developed through a trial-and-error process where combinations of plant or animal extracts were experimented with in vivo on human subjects. While such trials may have shown some therapeutic benefit, they most often resulted in no effect or adverse effects. Through these types of experiments, rudimentary medicinal knowledge was obtained. As technology advanced, complex mixtures of chemicals from extracts were separated and the individual components were tested for therapeutic value. In addition, animal models, such as rats, pigs, dogs, and mice, were harnessed to test the effects of isolated compounds before they were tried in humans. Bacteria and yeast were utilized in the drug discovery process, mainly as a method of producing complex organic molecules in large quantities for testing. Drug discovery took yet another turn with the advent of molecular biology and combinatorial chemistry. The combination of these technologies allowed for the development of specific compounds that bound to and affected the activity of individual proteins. The challenge in drug discovery was to choose the correct protein to target with compounds. The advancement of genetics in yeast, Caenorhabditis elegans, and Drosophila and the recognition that many biological mechanisms and protein functions have been highly conserved has led to their more recent integration into the drug discovery process. Bacteria, yeast, C. elegans, Drosophila, and mouse models all have a unique utility and history in drug discovery, and the combination of these systems is helping to drive the selection and validation of tomorrow's small molecule medicines.
Section snippets
Brief history
Bacteria have long been the subject of scientific study due to their ability to cause disease in humans (Lederberg, 2000). One of the major advances in the health and well-being of human civilizations was the development of the antibiotic. While the introduction of antibiotics had an enormous impact on the ability to treat bacterial infections, they continue to be the leading cause of death worldwide (Binder et al., 1999). Moreover, the effectiveness of antibiotics has been eroded by the
Yeast as a research organism
Saccharomyces cerevisiae, commonly known as baker's, brewer's, or budding yeast, has been the subject of study for over 100 years. The species has many features that endear it to scientists. Unlike a mouse, it produces a pleasing odor and can be left in a refrigerator or freezer for many months without complaint. It is nonpathogenic and divides every 2 hours, growing as dispersed cells in liquid or as colonies on solid media, and its nutrient requirements are very economical to satisfy. It can
Brief history
From the humble beginnings of a single landmark paper published by Brenner (1974) has grown an entire field of research into the small roundworm C. elegans. Having been born so recently as a research tool, C. elegans have much less of a history and tradition in drug discovery as have the model systems of yeast, bacteria, Drosophila, or even mice. Yet, this unique organism is poised to make an enormous impact in the future of drug discovery. C. elegans was the first multicellular organism to
Mouse models
Historically, drug discovery has consisted of a linear process whereby a large number of compounds are tested in relevant models. It is estimated that currently only 483 targets account for all drugs now on the market Drews, 2000, Reiss, 2001. The publication of human sequences has resulted in the availability of large amounts of data that are potentially directly relevant to the discovery of novel and useful drug targets, which will necessitate a change in this linear process. Of the ∼30,000
Conclusions and perspectives
The use of animal models in drug discovery is an essential component of the entire drug discovery process. Genetic models allow investigators to probe complex biological questions that would take many years to answer and in some cases would require experiments that are considered unethical in humans. Moving from the unicellular systems such as yeast to the relatively more cumbersome rodent models, one exchanges speed for relevance to human disease. Experiments done in yeast are often lightning
References (339)
- et al.
Bacterial virulence as a target for antimicrobial chemotherapy
Curr Opin Biotechnol
(2000) - et al.
Potential benefits of the irreversible pan-erbB inhibitor, CI-1033, in the treatment of breast cancer
Semin Oncol
(2002) New antibiotic discovery, novel screens, novel targets and impact of microbial genomics
Curr Opin Microbiol
(1998)- et al.
Critical contribution of linker proteins to Raf kinase activation
J Biol Chem
(2002) - et al.
A negative regulatory function for the protein tyrosine phosphatase PTP2C revealed by reconstruction of platelet-derived growth factor receptor signalling in Schizosaccharomyces pombe
FEBS Lett
(1998) - et al.
Electrophysiological methods
Methods Cell Biol
(1995) - et al.
A genomic screen identifies AUT8 as a novel gene essential for autophagy in the yeast Saccharomyces cerevisiae
Gene
(2001) GFP in Drosophila
Trends Genet
(1995)Therapeutic targets in radiotherapy
Int J Radiat Oncol Biol Phys
(2001)- et al.
Identification of novel pheromone-response regulators through systematic overexpression of 120 protein kinases in yeast
J Biol Chem
(2001)
dsRNA-mediated gene silencing in cultured Drosophila cells: a tissue culture model for the analysis of RNA interference
Gene
Flying from genes to drugs
Trends Mol Med
Fluoxetine-resistant mutants in C. elegans define a novel family of transmembrane proteins
Mol Cell
Phage display for target-based antibacterial drug discovery
Drug Discov Today
Applied genomics: integration of the technology within pharmaceutical research and development
Curr Opin Biotechnol
Gene expression profiling in the amygdala: an approach to examine the molecular substrates of mammalian behavior
Physiol Behav
The Bacillus subtilis genome project: aims and progress
Trends Biotechnol
Novel antifungal drugs
Curr Opin Microbiol
Comprehensive evaluation of isoprenoid biosynthesis regulation in Saccharomyces cerevisiae utilizing the Genome Reporter Matrix
J Lipid Res
Genetic balancers
Methods Cell Biol
Genetic control of programmed cell death in the nematode C. elegans
Cell
Comparing nuclear receptors in worms, flies and humans
Trends Pharmacol Sci
Methods of studying behavioral plasticity in Caenorhabditis elegans
Methods Cell Biol
Caenorhabditis elegans: how good a model for veterinary parasites?
Vet Parasitol
From sequence to phenotype: reverse genetics in Drosophila melanogaster
Nat Rev Genet
The genome sequence of Drosophila melanogaster
Science
Systematic identification of essential genes by in vitro mariner mutagenesis
Proc Natl Acad Sci USA
PCR-based subtractive hybridization and differences in gene content among strains of Helicobacter pylori
Proc Natl Acad Sci USA
Apoptotic molecular machinery: vastly increased complexity in vertebrates revealed by genome comparisons
Science
A genome-based approach for the identification of essential bacterial genes
Nat Biotechnol
Activation of phospholipase Cγ in Schizosaccharomyces pombe by coexpression of receptor or nonreceptor tyrosine kinases
Mol Cell Biol
Gene ontology: tool for the unification of biology. The Gene Ontology Consortium
Nat Genet
Studies on the chemical nature of the substance inducing transformation of pneumococcal types. Induction of transformation by a deoxyribonucleic acid fraction isolated from Pneumococcus type III
J Exp Med
CRITICA: coding region identification tool invoking comparative analysis
Mol Biol Evol
Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress
Nat Genet
Genome-wide expression patterns in Saccharomyces cerevisiae: comparison of drug treatments and genetic alterations affecting biosynthesis of ergosterol
Antimicrob Agents Chemother
Genetic and cellular analysis of behavior in C. elegans
Annu Rev Neurosci
A protein linkage map of Escherichia coli bacteriophage T7
Nat Genet
Functionally homologous cell cycle control genes in budding and fission yeast
Nature
Comparative genomics of BCG vaccines by whole-genome DNA microarray
Science
P-element-mediated enhancer detection: a versatile method to study development in Drosophila
Genes Dev
Genetic mapping with SNP markers in Drosophila
Nat Genet
Emerging infectious diseases: public health issues for the 21st century
Science
Yeast Saccharomyces cerevisiae as a model system to study the cytotoxic activity of the antitumor drug camptothecin
Cancer Chemother Pharmacol Suppl
A family of hexosephosphate mutases in Saccharomyces cerevisiae
Eur J Biochem
Combined functional genomic maps of the C. elegans DNA damage response
Science
Targeted gene expression as a means of altering cell fates and generating dominant phenotypes
Development
The genetics of Caenorhabditis elegans
Genetics
Concordance analysis of microbial genomes
Nucleic Acids Res
Dominant missense mutations in a novel yeast protein related to mammalian phosphatidylinositol 3-kinase and VPS34 abrogate rapamycin cytotoxicity
Mol Cell Biol
Cited by (44)
A Chemical Genomic Approach Identifies Matrix Metalloproteinases as Playing an Essential and Specific Role in Xenopus Melanophore Migration
2009, Chemistry and BiologyCitation Excerpt :Small molecule intervention offers a complimentary approach to loss-of-function mutations in the analysis of complex, multicomponent biological processes such as cell signaling and morphogenesis. Whole animal high-throughput chemical genomic screens have been developed for Drosophila, Caenorhabditis elegans, zebrafish, and Xenopus (Carroll et al., 2003; Kwok et al., 2006; Tomlinson et al., 2005; Zon and Peterson, 2005). An advantage of chemical genomic screens over mutagenesis screens is that they allow for temporal control of protein function.
Toxicogenomic predictive modeling: Emerging opportunities for more efficient drug discovery and development
2008, Technological Forecasting and Social ChangeInduction of biochemical stress markers and apoptosis in transgenic Drosophila melanogaster against complex chemical mixtures: Role of reactive oxygen species
2007, Chemico-Biological InteractionsCitation Excerpt :The model raises fewer ethical objections and falls within the recommendation of European Centre for the Validation of Alternative Methods (ECVAM) [16]. During the last decade, the model has been used extensively in toxicological studies [17,18] drug discovery, and in unraveling pathway genes of human disease [19]. Bg9 is a strain of Drosophila melanogaster transgenic for hsp70 used during the study.
Small molecule screening by imaging
2006, Current Opinion in Chemical BiologyControl of aging by the renin–angiotensin system: a review of C. elegans, Drosophila, and mammals
2022, Frontiers in PharmacologyAntimicrobial Compounds from Microorganisms
2022, Antibiotics