Georgia Tech researchers have developed a rapid high-throughput assay that can be used to screen pharmaceutical libraries to identify novel treatments for irritable bowel syndrome with constipation (IBS-C). Georgia Tech’s luciferase-based 5-HTR4b assay achieves a screening throughput of one compound per second, with an overall assay time of 2.5 hours. A major challenge in identifying novel treatments for IBS-C is a lack of serotonin receptor 4b (5-HTR4b) high-throughput assays to rapidly assess large libraries of chemicals. Currently, a 2-day culture time is required to test colon cell motility, which is time-prohibitive for a primary screen tool.
Using their G-protein coupled receptors (GPCR) assay, researchers screened more than 1,000 natural products and anti-infection agents and identified five previously unidentified 5-HTR4b ligands. The team validated three of the five ligands (hordenine, halofuginone, and revaprazon) as 5-HTR4b agonists, as they increase motility or wound healing in colon epithelial cells. Significantly, the increased assay signal of the luciferase reporter should enable the generation of other high-throughput GPCR-based assays.
- Powerful: Permits the rapid screening of pharmaceutical libraries to identify 5-HTR4b agonists as therapeutic candidates for IBS-C
- Efficient: Achieves a screening throughput of one compound per second
- Innovative: Enables screening of gut microbiota metabolites to further understand the link between the host and gut microbiome
- Drug discovery
In humans, 95 percent of 5-HT is found in the gastrointestinal tract, where its release and reception transmit information from the gut lumen to gut nerve cells and smooth muscles. Of the seven 5-HT receptor families, 5-HTR4 is broadly expressed in the gut—for example on neurons that control muscle contraction and relaxation—and has been implicated in IBS-C, which affects 15 percent of the world population. Agonists of 5-HTR4 are used for treatment of IBS, relieving constipation, abdominal pain, and bloating.