Chemical genetics

Chemical genetics is the investigation of the function of proteins and signal transduction pathways in cells by the screening of chemical libraries of small molecules.[1] Chemical genetics is analogous to classical genetic screen where random mutations are introduced in organisms, the phenotype of these mutants is observed, and finally the specific gene mutation (genotype) that produced that phenotype is identified. In chemical genetics, the phenotype is disturbed not by introduction of mutations, but by exposure to small molecule tool compounds. Phenotypic screening of chemical libraries is used to identify drug targets (forward genetics or chemoproteomics) or to validate those targets in experimental models of disease (reverse genetics).[2] Recent applications of this topic have been implicated in signal transduction, which may play a role in discovering new cancer treatments.[3] Chemical genetics can serve as a unifying study between chemistry and biology.[4][5] The approach was first proposed by Tim Mitchison in 1994 in an opinion piece in the journal Chemistry & Biology entitled "Towards a pharmacological genetics".[6]

Method

Chemical genetic screens are performed using libraries of small molecules that have known activities or simply diverse chemical structures. These screens can be done in a high-throughput mode, using 96 well-plates, where each well contains cells treated with a unique compound. In addition to cells, Xenopus or zebrafish embryos can also be screened in 96 well format where compounds are dissolved in the media in which embryos grow. Embryos are developed until the stage of interest and then the phenotype can be analyzed. Several concentrations can be tested in order to determine the toxic and the optimal concentrations.[7][8]

Applications

Adding compounds to developing embryos allow comprehension of mechanism of action of drugs, their toxicity and developmental processes involving their targets. Chemical screens have been mostly performed on either wild type or transgenic Xenopus and zebrafish organisms as they produce a large amount of synchronized, fast-to-develop and transparent eggs easy to visually score.[9][10] The use of chemicals in developmental biology offers two main advantages. Firstly, it is easy to perform high-throughput screen using wide spectrum or specific target compounds and reveal important genes or pathways involved in developmental processes. Secondly, it allows narrowing the time of action of a particular gene.[11] It can also be used as a tool in drug development to test toxicity in whole organism. Procedures such as FETAX (Frog Embryo Teratogenesis Assay – Xenopus) are being developed to implement chemical screenings to test toxicity.[12] Zebrafish and Xenopus embryos have also been used to identify new drugs targeting a particular gene of interest.[13]

See also

References
  1. Kubinyi H (2006). "Chemogenomics in drug discovery". In Weinmann H, Jaroch S (eds.). Chemical genomics small molecule probes to study cellular function. Berlin: Springer. ISBN 978-3-540-27865-8.
  2. Russel K, Michne WF (2004). "The value of chemical genetics in drug discovery". In Folkers G, Kubinyi H, Müller G, Mannhold R (eds.). Chemogenomics in drug discovery: a medicinal chemistry perspective. Weinheim: Wiley-VCH. pp. 69–96. ISBN 978-3-527-30987-0.
  3. Carlson SM, White FM (May 2012). "Expanding applications of chemical genetics in signal transduction". Cell Cycle. 11 (10): 1903–9. doi:10.4161/cc.19956. PMC 3359120. PMID 22544320.
  4. O'Connor CJ, Laraia L, Spring DR (Aug 2011). "Chemical genetics". Chemical Society Reviews. 40 (8): 4332–45. doi:10.1039/C1CS15053G. PMID 21562678.
  5. Branca M (Feb 2003). "Conquering Infinity with Chemical Genetics". Bio IT World.
  6. Mitchison, T. J. (1994). "Towards a pharmacological genetics". Chemistry & Biology. 1 (1): 3–6. doi:10.1016/1074-5521(94)90034-5. ISSN 1074-5521. PMID 9383364.
  7. Tomlinson ML, Rejzek M, Fidock M, Field RA, Wheeler GN (Apr 2009). "Chemical genomics identifies compounds affecting Xenopus laevis pigment cell development". Molecular BioSystems. 5 (4): 376–84. doi:10.1039/B818695B. PMID 19396374.
  8. Kälin RE, Bänziger-Tobler NE, Detmar M, Brändli AW (Jul 2009). "An in vivo chemical library screen in Xenopus tadpoles reveals novel pathways involved in angiogenesis and lymphangiogenesis". Blood. 114 (5): 1110–22. doi:10.1182/blood-2009-03-211771. PMC 2721788. PMID 19478043.
  9. Taylor KL, Grant NJ, Temperley ND, Patton EE (2010-06-12). "Small molecule screening in zebrafish: an in vivo approach to identifying new chemical tools and drug leads". Cell Communication and Signaling. 8 (1): 11. doi:10.1186/1478-811x-8-11. PMC 2912314. PMID 20540792.
  10. Ny A, Autiero M, Carmeliet P (Mar 2006). "Zebrafish and Xenopus tadpoles: small animal models to study angiogenesis and lymphangiogenesis". Experimental Cell Research. Special Issue on Angiogenesis. 312 (5): 684–93. doi:10.1016/j.yexcr.2005.10.018. PMID 16309670.
  11. Tomlinson ML, Guan P, Morris RJ, Fidock MD, Rejzek M, Garcia-Morales C, Field RA, Wheeler GN (Jan 2009). "A chemical genomic approach identifies matrix metalloproteinases as playing an essential and specific role in Xenopus melanophore migration". Chemistry & Biology. 16 (1): 93–104. doi:10.1016/j.chembiol.2008.12.005. PMID 19171309.
  12. Hu L, Zhu J, Rotchell JM, Wu L, Gao J, Shi H (Mar 2015). "Use of the enhanced frog embryo teratogenesis assay-Xenopus (FETAX) to determine chemically-induced phenotypic effects". The Science of the Total Environment. 508: 258–65. Bibcode:2015ScTEn.508..258H. doi:10.1016/j.scitotenv.2014.11.086. PMID 25481254.
  13. Molina G, Vogt A, Bakan A, Dai W, Queiroz de Oliveira P, Znosko W, Smithgall TE, Bahar I, Lazo JS, Day BW, Tsang M (Sep 2009). "Zebrafish chemical screening reveals an inhibitor of Dusp6 that expands cardiac cell lineages". Nature Chemical Biology. 5 (9): 680–7. doi:10.1038/nchembio.190. PMC 2771339. PMID 19578332.
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