Phenotypic screening

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.[1] Phenotypic screening must be followed up with identification (sometimes referred to as target deconvolution) and validation,[2] often through the use of chemoproteomics, to identify the mechanisms through which a phenotypic hit works.[3]

Historical context

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Phenotypic screening historically has been the basis for the discovery of new drugs.[4] Compounds are screened in cellular or animal disease models to identify compounds that cause a desirable change in phenotype. Only after the compounds have been discovered are efforts made to determine the biological targets of the compounds - a process known as target deconvolution. This overall strategy is referred to as "classical pharmacology", "forward pharmacology" or "phenotypic drug discovery" (PDD).[4]

More recently it has become popular to develop a hypothesis that a certain biological target is disease modifying, and then screen for compounds that modulate the activity of this purified target. Afterwards, these compounds are tested in animals to see if they have the desired effect. This approach is known as "reverse pharmacology" or "target based drug discovery" (TDD).[5] However recent statistical analysis reveals that a disproportionate number of first-in-class drugs with novel mechanisms of action come from phenotypic screening[6] which has led to a resurgence of interest in this method.[1][7][8]

Types

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In vitro

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The simplest phenotypic screens employ cell lines and monitor a single parameter such as cellular death or the production of a particular protein. High-content screening where changes in the expression of several proteins can be simultaneously monitored is also often used.[9][10] High-content imaging of dye-labeled cellular components can also reveal effects of compounds on cell cultures in vitro, distinguishing the phenotypic effects of a broad variety of drugs.[11]

In vivo

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In whole animal-based approaches, phenotypic screening is best exemplified where a substance is evaluated for potential therapeutic benefit across many different types of animal models representing different disease states.[12] Phenotypic screening in animal-based systems utilize model organisms to evaluate the effects of a test agent in fully assembled biological systems. Example organisms used for high-content screening include the fruit fly (Drosophila melanogaster), zebrafish (Danio rerio) and mice (Mus musculus).[13] In some instances the term phenotypic screening is used to include the serendipitous findings that occur in clinical trial settings particularly when new and unanticipated therapeutic effects of a therapeutic candidate are uncovered.[6]

Screening in model organism offers the advantage of interrogating test agents, or alterations in targets of interest, in the context of fully integrated, assembled, biological systems, providing insights that could otherwise not be obtained in cellular systems. Some have argued that cellular based systems are unable to adequately model human disease processes that involve many different cell types across many different organ systems and that this type of complexity can only be emulated in model organisms.[14][15] The productivity of drug discovery by phenotypic screening in organisms, including serendipitous findings in the clinic, are consistent with this notion.[6][16]

Use in drug repositioning

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Animal based approaches to phenotypic screening are not as amenable to screening libraries containing thousands of small molecules. Therefore, these approaches have found more utility in evaluating already approved drugs or late stage drug candidates for drug repositioning.[12]

A number of companies including Melior Discovery,[17][18] Phylonix, and Sosei have specialized in using phenotypic screening in animal disease models for drug positioning. Many other companies are involved in phenotypic screening research approaches, including Eurofins Discovery Phenotypic Services, Evotec, Dharmacon, Inc., ThermoScientific, Cellecta, and Persomics.

Collaborative research

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The pharmaceutical company Eli Lilly has formalized collaborative efforts with various 3rd parties aimed at conducting phenotypic screening of selected small molecules.[19]

References

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  1. ^ a b Kotz J (April 2012). "Phenotypic screening, take two". Science-Business EXchange. 5 (15): 380. doi:10.1038/scibx.2012.380.
  2. ^ Wilkinson IV, Terstappen GC, Russell AJ (September 2020). "Combining experimental strategies for successful target deconvolution". Drug Discovery Today. 25 (11): 1998–2005. doi:10.1016/j.drudis.2020.09.016. PMID 32971235. S2CID 221914342.
  3. ^ Moellering RE, Cravatt BF (January 2012). "How chemoproteomics can enable drug discovery and development". Chemistry & Biology. 19 (1): 11–22. doi:10.1016/j.chembiol.2012.01.001. PMC 3312051. PMID 22284350.
  4. ^ a b Vincent F, Nueda A, Lee J, Schenone M, Prunotto M, Mercola M (May 2022). "Phenotypic drug discovery: recent successes, lessons learned and new directions". Nature Reviews. Drug Discovery. doi:10.1038/s41573-022-00472-w. PMC 9708951. PMID 35637317. S2CID 249201045.
  5. ^ Lee JA, Uhlik MT, Moxham CM, Tomandl D, Sall DJ (May 2012). "Modern phenotypic drug discovery is a viable, neoclassic pharma strategy". Journal of Medicinal Chemistry. 55 (10): 4527–4538. doi:10.1021/jm201649s. PMID 22409666.
  6. ^ a b c Swinney DC, Anthony J (June 2011). "How were new medicines discovered?". Nature Reviews. Drug Discovery. 10 (7): 507–519. doi:10.1038/nrd3480. PMID 21701501. S2CID 19171881.
  7. ^ Zheng W, Thorne N, McKew JC (November 2013). "Phenotypic screens as a renewed approach for drug discovery". Drug Discovery Today. 18 (21–22): 1067–1073. doi:10.1016/j.drudis.2013.07.001. PMC 4531371. PMID 23850704.
  8. ^ Brown DG, Wobst HJ (March 2020). "Opportunities and Challenges in Phenotypic Screening for Neurodegenerative Disease Research". Journal of Medicinal Chemistry. 63 (5): 1823–1840. doi:10.1021/acs.jmedchem.9b00797. PMID 31268707. S2CID 195798523.
  9. ^ Haney SA, ed. (2008). High content screening: science, techniques and applications. New York: Wiley-Interscience. ISBN 978-0-470-03999-1.
  10. ^ Giuliano KA, Haskins JR, ed. (2010). High Content Screening: A Powerful Approach to Systems Cell Biology and Drug Discovery. Totowa, NJ: Humana Press. ISBN 978-1-61737-746-4.
  11. ^ Willis C, Nyffeler J, Harrill J (August 2020). "Phenotypic Profiling of Reference Chemicals across Biologically Diverse Cell Types Using the Cell Painting Assay". SLAS Discovery. 25 (7): 755–769. doi:10.1177/2472555220928004. PMC 9710725. PMID 32546035. S2CID 219726081.
  12. ^ a b Barrett MJ, Frail DE, ed. (2012). "PhenotypicIn VivoScreening to Identify New, Unpredicted Indications for Existing Drugs and Drug Candidates". Drug repositioning: Bringing new life to shelved assets and existing drugs. Hoboken, NJ: John Wiley & Sons. pp. 253–290. doi:10.1002/9781118274408.ch9. ISBN 978-0-470-87827-9.
  13. ^ Wheeler GN, Tomlinson RA (2012). Phenotypic screens with model organisms. New York, NY: Cambridge University Press. ISBN 978-0521889483.
  14. ^ Hellerstein MK (April 2008). "Exploiting complexity and the robustness of network architecture for drug discovery". The Journal of Pharmacology and Experimental Therapeutics. 325 (1): 1–9. doi:10.1124/jpet.107.131276. PMID 18202293. S2CID 36819512.
  15. ^ Hellerstein MK (January 2008). "A critique of the molecular target-based drug discovery paradigm based on principles of metabolic control: advantages of pathway-based discovery". Metabolic Engineering. 10 (1): 1–9. doi:10.1016/j.ymben.2007.09.003. PMID 17962055.
  16. ^ Saporito MS, Reaume AG (2011). "theraTRACE®: A mechanism unbiased in vivo platform for phenotypic screening and drug repositioning". Drug Discovery Today: Therapeutic Strategies. 8 (2): 89–95. doi:10.1016/j.ddstr.2011.06.002.
  17. ^ "Melior Discovery website".
  18. ^ "Therapeutic Drug Repurposing, Repositioning and Rescue Part II: Business Review". Drug Discovery World. 6 April 2015. Retrieved 1 May 2015.
  19. ^ "Open Innovation Drug Discovery - What are PD2 and TargetD2?". Eli Lilly & Company. Archived from the original on 2012-01-30. Retrieved 2012-06-04.

Further reading

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