Addressing the Challenges of Drug Development
Drug development is a complex process, often requiring over a decade and substantial financial investment. Drug repurposing (also known as drug repositioning), which involves finding new therapeutic applications for existing drugs, provides a strategic alternative that significantly shortens timelines and reduces costs. By leveraging pre-existing safety data, repurposing bypasses many early-stage hurdles, accelerating the discovery of effective treatments (1). In drug repurposing, the time required for development can be reduced to approximately 25% of the typical duration, while costs may decrease to 1-2% of the usual drug development expenses. (2). This approach has been particularly pivotal during health crises, such as the COVID-19 pandemic, when rapid therapeutic solutions were urgently needed (3).
Enter zebrafish larvae—a model organism offering unique advantages, including high-throughput screening capabilities and early-stage testing within days of fertilization. These attributes make zebrafish larvae a game-changer in drug repurposing.
Rather than beginning with in-vitro assays, researchers can directly utilize a zebrafish model to identify potential hits. Zebrafish larvae can be utilized to explore the potential repurposing of existing drugs for new therapeutic applications. By using an appropriate model, zebrafish larvae can be exposed to approved drugs originally developed for different therapeutic applications, allowing us to assess their effects on various disease models and potentially uncover new uses. If an effective drug is identified for a different disease, the clinical trial process can be accelerated, as the safety of the drug has already been established.
Below, we outline three key advantages of using zebrafish larvae in drug repurposing:
1) Early Hit Identification: Finding Effective Candidates Quickly
The drug repurposing process relies on identifying “hits”—compounds showing promising biological activity against a target condition. Zebrafish larvae allow researchers to assess hits in a short period of time. Zebrafish embryos develop externally and rapidly, reaching critical stages for testing (2–6 days post-fertilization depending on disease model). During this window, their transparency allows researchers to visually monitor organ development, neural activity, and even responses to drugs in real time. Using advanced imaging techniques, molecular markers, and behavioral tracking systems, researchers can observe the effects of drugs on target tissues or disease pathways in vivo. For instance, neurological disorders can be studied by evaluating changes in larvae behavior or neural signaling, providing insights into a drug’s efficacy and safety (4).
2) High-Throughput Screening: Speed Meets Efficiency
One of the most remarkable features of zebrafish larvae is their suitability for high-throughput screening. The ability to house larvae in multi-well plates enables simultaneous testing of hundreds to thousands of compounds, dramatically accelerating the drug discovery pipeline. Furthermore, very low amount of the drug is needed in high-throughput screening. This scalability is especially advantageous for repurposing, where researchers aim to screen libraries of FDA-approved drugs or other known compounds for new indications (5 and 6).
3) Phenotypic Assay: Enhancing Drug Discovery Success
Research suggests that phenotypic screening can yield success rates for hit identification that are nearly double those of target-based approaches. By embracing the complexity of biological systems, phenotypic methods enable the discovery of compounds that operate through novel mechanisms, often uncovering unexpected therapeutic possibilities.
An exciting advancement in phenotypic screening is the use of zebrafish larvae as a model organism. Zebrafish have emerged as a powerful tool in preclinical drug discovery, thanks to their small size, rapid development, and transparent embryos, which enable real-time visualization of biological processes. As a result, zebrafish larvae are increasingly employed in phenotypic assays to assess the effects of drug candidates on development, behavior, and various disease models (7).
In summary, drug repurposing, significantly reduces timelines and expenses in the process of drug discovery. Zebrafish larvae play a crucial role in this process by enabling early hit identification due to their nature, which allows us to perform phenotypic assays in a high-throughput format. By leveraging zebrafish larvae, researchers can accelerate the repurposing of existing drugs, potentially transforming the drug development landscape, especially in urgent health crises.
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
- Nosengo, N. (2016) Can you teach old drugs new tricks? Nature, 534, 314–316
- Zheng, W., Thorne, N., & McKew, J. C. (2013). “Phenotypic screens as a renewed approach for drug discovery.” Drug Discovery Today, 18(0), 1067–1073
- Mahdi, M., Hermán, L., Réthelyi, J. M., & Bálint, B. L. (2022). “Potential role of the antidepressants fluoxetine and fluvoxamine in the treatment of COVID-19.” International Journal of Molecular Sciences, 23(7), 3812
- Ren, Q., Jiang, X., Zhang, S., Gao, X., Paudel, Y. N., Zhang, P., Wang, R., Liu, K., & Jin, M. (2022). Neuroprotective effect of YIAEDAER peptide against Parkinson’s disease-like pathology in zebrafish. Biomedicine & Pharmacotherapy, 147, 112629
- Griffin, A., Anvar, M., Hamling, K., & Baraban, S. C. (2020). “Phenotype-based screening of synthetic cannabinoids in a Dravet syndrome zebrafish model.” Frontiers in Pharmacology, 11, 464
- Feng, Z., Lin, C., Tu, L., Su, M., Song, C., Liu, S., Suryanto, M. E., Hsiao, C.-D., & Li, L. (2021). FDA-approved drug screening for compounds that facilitate hematopoietic stem and progenitor cells (HSPCs) expansion in zebrafish. Cells, 10(8), 2149
- 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
Keywords
Drug development, drug repurposing, therapeutic applications, zebrafish larvae, model organism, high-throughput screening, early-stage testing, pre-existing safety data, drug discovery, disease models, clinical trial, organ development, neural activity, real-time monitoring, molecular markers, behavioral tracking, neurological disorders, drug efficacy, phenotypic screening, target-based approaches, phenotypic assays, FDA-approved drugs, preclinical drug discovery, zebrafish-based assays, drug discovery pipeline, compound efficacy, toxicology services