Drug discovery and chemical probing inDrosophila

Abstract

Flies are increasingly utilized in drug discovery and chemical probing in vivo, which are novel technologies complementary to genetic probing in fundamental biological studies. Excellent genetic conservation, small size, short generation time and over one hundred years of genetics make Drosophila an attractive model for rapid assay readout and use of analytical amounts of compound, enabling the experimental iterations needed in early drug development at a fraction of time and costs. Here, we describe an effective drug-testing pipeline using adult flies that can be easily implemented to study several disease models and different genotypes to discover novel molecular insight, probes, quality lead compounds, and develop novel prototype drugs.

Modeling Neoplastic Growth in Renal Cell Carcinoma and Polycystic Kidney Disease

“…However, that renal cysts can form in Drosophila corroborates the growing evidence that the role of cilia may need re-examination. Finally, the cystic flies also exhibited similar pharmacological response to rapamycin and new mimetics of the second mitochondria-derived activator of caspases (Smac) [200,201]. Discussed in more detail in Section 10.1, administration of the active Smac mimics, reduced cysts of the renal tubule both numerically and in size (Figure 3c) [200].…”

“…Discussed in more detail in Section 10.1, administration of the active Smac mimics, reduced cysts of the renal tubule both numerically and in size (Figure 3c) [200]. Note, cyst reduction can be quantified with a "cystic index" in fly and mammalian PKD models [200,201] (also see Section 10). ).…”

“…Results were then analyzed statistically to derive a "cystic index" used to compare treatments [200]. For a discussion of the cystic index in the fly model, see [201]. Upon Smac treatment, the BicC mutants displayed a significant overall reduction of cysts, and differential compound efficacy [200].…”

Cyst Reduction by Melatonin in a Novel Drosophila Model of Polycystic Kidney Disease

“…Therefore, melatonin by lowering oxidative damage to the renal tubular cells, may similarly improve cysts in both mammalian and Drosophila renal tubules. Here, we report that melatonin exhibits cyst-reducing effects in the first-in-kind Drosophila model of PKD [ 21 , 27 , 30 , 31 ].…”

“…In the fly, these are called proximal, intermediate, and terminal (reviewed in [ 27 ]). Unlike the human nephron, the Drosophila Malpighian tubules can be precisely dissected and examined to evaluate cyst-reducing molecules [ 27 , 30 , 31 ].…”