In the complex landscape of drug development, researchers continually seek strategies to improve the success rates of identifying effective therapeutic candidates. Traditional target-based approaches have long dominated the field, focusing on specific molecular targets and their interactions with potential drugs. However, emerging evidence suggests that phenotypic screening—an approach that evaluates the biological effects of compounds in relevant cellular or organismal contexts—may significantly enhance the likelihood of discovering viable drug candidates.
Studies indicate that phenotypic screening can lead to hit identification success rates nearly two times higher than those achieved through target-based methods (Zheng, W. et al, 2013). By capturing the complexity of biological systems, phenotypic approaches allow for the discovery of compounds acting through novel mechanisms, often revealing unexpected therapeutic opportunities.
One particularly promising advancement in phenotypic screening is the utilization of zebrafish larvae as a model organism. Zebrafish (Danio rerio) have become a valuable tool in preclinical drug discovery due to their small size, rapid development, and transparent embryos, which allow real-time visualization of biological processes. Zebrafish larvae are increasingly being used as a phenotypic assay to evaluate the effects of drug candidates on development, behavior, and disease models (Patton, E.E. et al, 2021).
Zebrafish larvae are ideal for high-throughput screening of small molecules because of their well-documented genetic tractability and the ability to model a wide range of human diseases, including cardiovascular diseases, neurodegenerative conditions, and cancers. The transparency of the larvae allows for non-invasive imaging of key physiological events, such as cardiac function, blood vessel formation, and neuronal development, making them an excellent platform for studying compound effects in vivo at early stages of development (Zon, L.I., & Peterson, R.T., 2005).
Studies have demonstrated that zebrafish larvae can provide early insights into compound efficacy and toxicity, offering a more comprehensive evaluation than in vitro assays alone. For example, the model has been used to assess the effects of the drug candidate for neurological disorders, cardiovascular diseases, cancers etc. (Dash, SN., & Patnaik, L., 2023).
The use of zebrafish larvae in preclinical drug discovery also addresses a key challenge in the field: the high rate of drug failure due to insufficient early-stage testing. By enabling rapid, cost-effective screening of large compound libraries, zebrafish larvae assays can identify lead candidates earlier in the drug development process and provide crucial data on pharmacokinetics, drug metabolism, and potential side effects.
Zebrafish larvae are increasingly recognized as a powerful tool for precision medicine, particularly in the context of neurological disorders. Their genetic tractability, rapid development, and transparent embryos allow researchers to model disease-specific phenotypes, such as those seen in neurodegenerative diseases. This enables personalized drug screening, where compounds can be tested on models that mimic individual genetic variations, offering a more tailored approach to therapeutic development (Ochenkowska K. et al, 2022).
Incorporating zebrafish larvae into phenotypic screening platforms not only complements traditional approaches but also provides a more holistic understanding of drug action in vivo. As the field evolves, the integration of zebrafish assays with other high-content screening methods is expected to accelerate the identification of novel drug candidates and enhance the translation of preclinical findings into successful clinical outcomes.
The Zebrafish Centre for Drug Discovery at CREM Co Labs utilizes zebrafish models for a broad range of drug discovery and toxicology services. For clients seeking efficient and cost-effective preclinical testing, CREM Co Labs offers cutting-edge zebrafish-based assays that provide valuable insights into compound efficacy and toxicity.
References:
Zheng, W., Thorne, N., & McKew, J. C. (2013). “Phenotypic screens as a renewed approach for drug discovery.” Drug Discovery Today, 18(0), 1067–1073.
Patton, E. E., Zon, L. I., & Langenau, D. M. (2021). “Zebrafish disease models in drug discovery: from preclinical modelling to clinical trials.” Nature Reviews Drug Discovery, 20(8), 611–628
Zon, L. I., & Peterson, R. T. (2005). “In vivo drug discovery in the zebrafish.” Nature Reviews Drug Discovery, 4(1), 35–44
Dash, S. N., & Patnaik, L. (2023). “Flight for fish in drug discovery: A review of zebrafish-based screening of molecules.” Biology Letters, 19(8), 20220541.
Ochenkowska, K., Herold, A., & Samarut, É. (2022). “Zebrafish Is a Powerful Tool for Precision Medicine Approaches to Neurological Disorders.” Frontiers in Neurology, 13, 919447.