Chemical genetics

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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]

Contents

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

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<span class="mw-page-title-main">Zebrafish</span> Species of fish

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<i>Xenopus</i> Genus of amphibians

Xenopus is a genus of highly aquatic frogs native to sub-Saharan Africa. Twenty species are currently described within it. The two best-known species of this genus are Xenopus laevis and Xenopus tropicalis, which are commonly studied as model organisms for developmental biology, cell biology, toxicology, neuroscience and for modelling human disease and birth defects.

A genetic screen or mutagenesis screen is an experimental technique used to identify and select individuals who possess a phenotype of interest in a mutagenized population. Hence a genetic screen is a type of phenotypic screen. Genetic screens can provide important information on gene function as well as the molecular events that underlie a biological process or pathway. While genome projects have identified an extensive inventory of genes in many different organisms, genetic screens can provide valuable insight as to how those genes function.

<span class="mw-page-title-main">Drug discovery</span> Pharmaceutical procedure

In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered.

<span class="mw-page-title-main">High-throughput screening</span> Drug discovery technique

High-throughput screening (HTS) is a method for scientific discovery especially used in drug discovery and relevant to the fields of biology, materials science and chemistry. Using robotics, data processing/control software, liquid handling devices, and sensitive detectors, high-throughput screening allows a researcher to quickly conduct millions of chemical, genetic, or pharmacological tests. Through this process one can quickly recognize active compounds, antibodies, or genes that modulate a particular biomolecular pathway. The results of these experiments provide starting points for drug design and for understanding the noninteraction or role of a particular location.

<span class="mw-page-title-main">Medicinal chemistry</span> Scientific branch of chemistry

Medicinal or pharmaceutical chemistry is a scientific discipline at the intersection of chemistry and pharmacy involved with designing and developing pharmaceutical drugs. Medicinal chemistry involves the identification, synthesis and development of new chemical entities suitable for therapeutic use. It also includes the study of existing drugs, their biological properties, and their quantitative structure-activity relationships (QSAR).

<span class="mw-page-title-main">Morpholino</span> Chemical compound

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Timothy John Mitchison is a cell biologist and systems biologist and Hasib Sabbagh Professor of Systems Biology at Harvard Medical School in the United States. He is known for his discovery, with Marc Kirschner, of dynamic instability in microtubules, for studies of the mechanism of cell division, and for contributions to chemical biology.

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Stuart Schreiber, Ph.D. is the Morris Loeb Research Professor at Harvard University, a co-Founder of the Broad Institute, Howard Hughes Medical Institute Investigator, Emeritus, and a member of the National Academy of Sciences and National Academy of Medicine. His work integrates chemical biology and human biology to advance the science of therapeutics. Key advances include the discovery that small molecules can function as “molecular glues” that promote protein–protein interactions, the co-discovery of mTOR and its role in nutrient-response signaling, the discovery of histone deacetylases and the demonstration that chromatin marks regulate gene expression, the development and application of diversity-oriented synthesis to microbial therapeutics, and the discovery of vulnerabilities of cancer cells linked to genetic, lineage and cell-state features, including ferroptotic vulnerabilities. His notable awards include the Wolf Prize in Chemistry and the Arthur Cope Award. His approach to discovering new therapeutics guided many biotechnology companies that he founded, including Vertex Pharmaceuticals and Ariad Pharmaceuticals. He has founded or co-founded 14 biotechnology companies, which have developed 16 first-in-human approved drugs or advanced clinical candidates.

<span class="mw-page-title-main">Mechanism of action</span> Biochemical interaction through which a drug produces its pharmacological effect

In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targets to which the drug binds, such as an enzyme or receptor. Receptor sites have specific affinities for drugs based on the chemical structure of the drug, as well as the specific action that occurs there.

<span class="mw-page-title-main">Chemogenomics</span>

Chemogenomics, or chemical genomics, is the systematic screening of targeted chemical libraries of small molecules against individual drug target families with the ultimate goal of identification of novel drugs and drug targets. Typically some members of a target library have been well characterized where both the function has been determined and compounds that modulate the function of those targets have been identified. Other members of the target family may have unknown function with no known ligands and hence are classified as orphan receptors. By identifying screening hits that modulate the activity of the less well characterized members of the target family, the function of these novel targets can be elucidated. Furthermore, the hits for these targets can be used as a starting point for drug discovery. The completion of the human genome project has provided an abundance of potential targets for therapeutic intervention. Chemogenomics strives to study the intersection of all possible drugs on all of these potential targets.

High-content screening (HCS), also known as high-content analysis (HCA) or cellomics, is a method that is used in biological research and drug discovery to identify substances such as small molecules, peptides, or RNAi that alter the phenotype of a cell in a desired manner. Hence high content screening is a type of phenotypic screen conducted in cells involving the analysis of whole cells or components of cells with simultaneous readout of several parameters. HCS is related to high-throughput screening (HTS), in which thousands of compounds are tested in parallel for their activity in one or more biological assays, but involves assays of more complex cellular phenotypes as outputs. Phenotypic changes may include increases or decreases in the production of cellular products such as proteins and/or changes in the morphology of the cell. Hence HCA typically involves automated microscopy and image analysis. Unlike high-content analysis, high-content screening implies a level of throughput which is why the term "screening" differentiates HCS from HCA, which may be high in content but low in throughput.

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<span class="mw-page-title-main">ChEMBL</span> Chemical database of bioactive molecules also having drug-like properties

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Phenotypic screening is a type of screening used in biological research and drug discovery to identify substances such as small molecules, peptides, or RNAi that alter the phenotype of a cell or an organism in a desired manner. Phenotypic screening must be followed up with identification and validation, often through the use of chemoproteomics, to identify the mechanisms through which a phenotypic hit works.

<span class="mw-page-title-main">Classical pharmacology</span> Drug discovery by phenotypic screening

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Chemoproteomics entails a broad array of techniques used to identify and interrogate protein-small molecule interactions. Chemoproteomics complements phenotypic drug discovery, a paradigm that aims to discover lead compounds on the basis of alleviating a disease phenotype, as opposed to target-based drug discovery, in which lead compounds are designed to interact with predetermined disease-driving biological targets. As phenotypic drug discovery assays do not provide confirmation of a compound's mechanism of action, chemoproteomics provides valuable follow-up strategies to narrow down potential targets and eventually validate a molecule's mechanism of action. Chemoproteomics also attempts to address the inherent challenge of drug promiscuity in small molecule drug discovery by analyzing protein-small molecule interactions on a proteome-wide scale. A major goal of chemoproteomics is to characterize the interactome of drug candidates to gain insight into mechanisms of off-target toxicity and polypharmacology.

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Hazel L. Sive is a South African-born biologist and educator. She is Dean of the College of Science, and Professor of Biology at Northeastern University. Sive is a research pioneer, award-winning educator and innovator in the higher education space who was elected as a Fellow of the American Association for the Advancement of Science in November 2021. Prior to June 2020, she was a Member of Whitehead Institute for Biomedical Research, Professor of Biology at Massachusetts Institute of Technology and Associate Member of the Broad Institute of MIT and Harvard. Sive studies development of the vertebrate embryo, and has made unique contributions to understanding how the face forms and how the brain develops its structure. Her lab also seeks to understand the origins of neurological and neurodevelopmental disorders, such as epilepsy, autism, Pitt–Hopkins syndrome and 16p11.2 deletion syndrome.

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. Archived from the original on 2023-03-17. Retrieved 2020-03-27.
  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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