fbpx
Wikipedia

Phenotypic screening

February 08, 2023

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

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

In vitro

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

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

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

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

References

  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. 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. 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. ^ . Eli Lilly & Company. Archived from the original on 2012-01-30. Retrieved 2012-06-04.

Further reading

  • Moffat JG, Rudolph J, Bailey D (August 2014). "Phenotypic screening in cancer drug discovery - past, present and future". Nature Reviews. Drug Discovery. 13 (8): 588–602. doi:10.1038/nrd4366. PMID 25033736. S2CID 5964541.
  • Mullard A (December 2015). "The phenotypic screening pendulum swings". Nature Reviews. Drug Discovery. 14 (12): 807–809. doi:10.1038/nrd4783. PMID 26620403. S2CID 19367768.

February 08, 2023
phenotypic, screening, type, screening, used, biological, research, drug, discovery, identify, substances, such, small, molecules, peptides, rnai, that, alter, phenotype, cell, organism, desired, manner, must, followed, with, identification, sometimes, referre. 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 Contents 1 Historical context 2 Types 2 1 In vitro 2 2 In vivo 3 Use in drug repositioning 4 Collaborative research 5 References 6 Further readingHistorical context EditPhenotypic 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 EditIn vitro Edit 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 Edit 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 EditAnimal 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 EditThe pharmaceutical company Eli Lilly has formalized collaborative efforts with various 3rd parties aimed at conducting phenotypic screening of selected small molecules 19 References Edit a b Kotz J April 2012 Phenotypic screening take two Science Business EXchange 5 15 380 doi 10 1038 scibx 2012 380 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 Moellering RE Cravatt BF January 2012 How chemoproteomics can enable drug discovery and development Chemistry amp Biology 19 1 11 22 doi 10 1016 j chembiol 2012 01 001 PMC 3312051 PMID 22284350 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 PMID 35637317 S2CID 249201045 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 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 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 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 Haney SA ed 2008 High content screening science techniques and applications New York Wiley Interscience ISBN 978 0 470 03999 1 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 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 PMID 32546035 S2CID 219726081 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 amp Sons pp 253 290 doi 10 1002 9781118274408 ch9 ISBN 978 0 470 87827 9 Wheeler GN Tomlinson RA 2012 Phenotypic screens with model organisms New York NY Cambridge University Press ISBN 978 0521889483 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 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 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 Melior Discovery website Therapeutic Drug Repurposing Repositioning and Rescue Part II Business Review Drug Discovery World 6 April 2015 Retrieved 1 May 2015 Open Innovation Drug Discovery What are PD2 and TargetD2 Eli Lilly amp Company Archived from the original on 2012 01 30 Retrieved 2012 06 04 Further reading EditMoffat JG Rudolph J Bailey D August 2014 Phenotypic screening in cancer drug discovery past present and future Nature Reviews Drug Discovery 13 8 588 602 doi 10 1038 nrd4366 PMID 25033736 S2CID 5964541 Mullard A December 2015 The phenotypic screening pendulum swings Nature Reviews Drug Discovery 14 12 807 809 doi 10 1038 nrd4783 PMID 26620403 S2CID 19367768 Retrieved from https en wikipedia org w index php title Phenotypic screening amp oldid 1136201821, wikipedia, wiki, book, books, library,

article

, read, download, free, free download, mp3, video, mp4, 3gp, jpg, jpeg, gif, png, picture, music, song, movie, book, game, games.