Drosophila Application in Drug Discovery
Drug development is a lengthy process associated with high costs and high failure rates. Drosophila has great potential as a highly functionally conserved human disease model for drug screening, validation and drug optimization, to efficiently identify potential drugs. In addition, economical Drosophila models with powerful features, further reduce the duration and cost of the drug discovery process.
Advantages of Drosophila as a Drug Discovery Model
Drug discovery is an important step in drug development and often determines the success. Drosophila has an inherent advantage in being a non-mammalian model for drug screening and validation.
1) Around 60% of human disease-associated genes are predicted to be direct homologs in Drosophila, and the degree of overall protein conservation is significant. Thus, this model has a potential for widespread drug discovery.
2) Sixty known drugs with important markets were found to have the same molecular mechanism of action in the Drosophila model, including actin and microtubule toxicants, kinases, phosphatases and membrane channel modulators. The accuracy and feasibility of the in vivo Drosophila model in simplifying drug screening is illustrated.
3) Using genetic techniques, more complex polygenic models can be developed in Drosophila. Compounds with better whole-animal efficacy and reduced whole-animal toxicity can be identified. The development time and cost are greatly reduced compared to the traditional drug screening route in the mouse model.
Drosophila Applications in Drug Discovery
Currently, although Drosophila models are in their infancy as drug discovery platforms, relevant results have been achieved in the fields, such as multiple endocrine neoplasia type 2 (MEN2), fragile X syndrome, epithelial malignant growth, intestinal stem cell-derived tumors, and combination therapies. In particular, anti-cancer drug development has already resulted in FDA approval using Drosophila drug screen models. The following is an example of the application of fruit flies for the development of anti-cancer drugs.
- Drug Screening
High-throughput screening is well established in Drosophila, allowing rapid and economical screening of novel drug candidates in a large compound library and reducing post-development costs. This in vivo multicellular environment restores intercellular interactions as much as possible and helps to identify drug candidates in the appropriate physiological and pathophysiological environment, reducing false positives and improving drug development success rates. Drosophila can not only perform forward screening but also reverse screening of known disease targets through special humanized models.
- Drug Validation
The targets of drug therapy often involve various cellular signaling and metabolic pathways. In the case of cancer, for example, these include enzymes, receptors, protein kinases, transcription factors, cell polarity regulators, and others. All of those can be manipulated in Drosophila inducing cancers by precision genetic techniques using overexpression, suppression, or mutations in specific genes/pathways, and subsequently tested for drug efficacy and precise pharmacological evaluation.
- Drug Optimization
Drosophila, a model organism with complex physiological metabolic reactions, also has potential in optimizing drug processes. By combining Drosophila genetics and medicinal chemistry, existing anticancer compounds can be improved and molecular entities can be rapidly optimized to reduce drug side effects without weakening therapeutic properties.
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- Dar AC, et al. (2012). Chemical genetic discovery of targets and anti-targets for cancer polypharmacology. Nature, 486(7401), 80-84.
- Fernández‐Hernández I, et al. (2016). The translational relevance of Drosophila in drug discovery. EMBO reports, 17(4), 471-472.
- Yadav AK, et al. (2016). Cancer drug development using drosophila as an in vivo tool: from bedside to bench and back. Trends in Pharmacological Sciences, 37(9), 789-806.
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