An assessment of the translational relevance of Drosophila in drug discovery

ABSTRACT

Introduction: Drosophila melanogaster offers a powerful expedient and economical system with facile genetics. Because of the high sequence and functional conservation with human disease-associated genes, it has been cardinal in deciphering disease mechanisms at the genetic and molecular level. Drosophila are amenable to and respond well to pharmaceutical treatment which coupled to their genetic tractability has led to discovery, repositioning, and validation of a number of compounds.

Areas covered: This review summarizes the generation of fly models of human diseases, their advantages and use in elucidation of human disease mechanisms. Representative studies provide examples of the utility of this system in modeling diseases and the discovery, repositioning and testing on pharmaceuticals to ameliorate them.

Expert opinion: Drosophila offers a facile and economical whole animal system with many homologous organs to humans, high functional conservation and established methods of generating and validating human disease models. Nevertheless, it remains relatively underused as a drug discovery tool probably because its relevance to mammalian systems remains under question. However, recent exciting success stories using Drosophila disease models for drug screening, repositioning and validation strongly suggest that fly models should figure prominently in the drug discovery pipeline from bench to bedside.

KEYWORDS:

• Disease models
• Drosophila
• pharmaceuticals
• translational relevance

Article highlights

• Appreciation of the potential and actual contributions of Drosophila melanogaster in the drug discovery process became apparent upon the realization that multiple molecular and cellular pathways were conserved between flies and mammals.

• Representative and highly relevant Drosophila models of human disease are expediently engineered either by overexpression of a human disease-associated gene, or by spatiotemporal-specific attenuation of the fly orthologue.

• The advantages of the short life cycle and genetic tractability of Drosophila, are capitalized upon in whole animal drug screen studies based on unambiguous phenotypic readouts of toxicity and easily quantifiable developmental and behavioral alterations.

• Drosophila models of human disease have contributed to drug discovery via target-identification, in vivo validation of known drugs and in vivo high-throughput compound screenings.

• To increase the contribution of Drosophila disease models in drug screening applications follow-up studies in mammalian species are essential to demonstrate conserved compound activities across several systems. This will likely improve acceptance of the relevance of fly models in the drug discovery process and expedite translation of lead compounds into human therapeutics.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

K Papanikolopoulou is supported by the Stavros Niarchos Foundation while EMC Skoulakis is supported through the project ‘Strategic Development of the Biomedical Research Institute “Alexander Fleming”’ (MIS 5002562) which is implemented under the ‘Action for the Strategic Development on the Research and Technological Sector’, funded by the Operational Programme ‘Competitiveness, Entrepreneurship and Innovation’ (NSRF 2014-2020) and co-financed by Greece and the European Union (European Regional Development Fund).