Small molecule drug screening in Drosophila identifies the 5HT2A receptor as a feeding modulation target

TLDR

Dysregulation of eating behavior leads to obesity, affecting 10 % of adults worldwide and causing nearly 3 million deaths annually. The study aimed to create a high‑throughput Drosophila larval screen for drugs that modulate food intake. The screen tested 3 630 small molecules, and cell‑based assays showed that metitepine antagonizes all five Drosophila 5‑HT receptors, with 5‑HT2A identified as the sole target for feeding inhibition. Metitepine potently reduces feeding in flies, highlighting conserved appetite‑regulating mechanisms and providing a platform for unbiased whole‑organism drug discovery.

Abstract

Dysregulation of eating behavior can lead to obesity, which affects 10% of the adult population worldwide and accounts for nearly 3 million deaths every year. Despite this burden on society, we currently lack effective pharmacological treatment options to regulate appetite. We used Drosophila melanogaster larvae to develop a high-throughput whole organism screen for drugs that modulate food intake. In a screen of 3630 small molecules, we identified the serotonin (5-hydroxytryptamine or 5-HT) receptor antagonist metitepine as a potent anorectic drug. Using cell-based assays we show that metitepine is an antagonist of all five Drosophila 5-HT receptors. We screened fly mutants for each of these receptors and found that serotonin receptor 5-HT2A is the sole molecular target for feeding inhibition by metitepine. These results highlight the conservation of molecular mechanisms controlling appetite and provide a method for unbiased whole-organism drug screens to identify novel drugs and molecular pathways modulating food intake.