Novel GPCR ligands: GPR120 case study


Novel GPCR ligands: GPR120 case study


D McCullough1; S A Trim1; S Baker1; P Grant1
1 Venomtech Limited, UK


GPR120 (FFAR4) is a free fatty acid receptor that stimulates incretin hormone release from colonic endocrine cells and is implicated in macrophage and adipocyte function. GPR120 activation has been linked with inhibition of inflammation, modulation of hormone secretion from the pancreas and gastrointestinal tract, and the regulation of lipid and/or glucose metabolism in adipose, liver, and muscle tissues. GPR120 agonism correlates with prevention of the occurrence and development of metabolic disorders such as obesity and diabetes. Natural ligands to GPR120 are free fatty acids, which do not make good drug candidates. Previous published attempts to identify agonists from compound libraries failed, making this a challenging and interesting receptor for drug discovery and novel drug candidates.
Venom peptides have evolved in many venomous genera to enable them to undertake both effective predation of prey and defence against their own predators. Venom peptides are secreted into the lumen of the venom gland and stored ready for rapid delivery in under seconds and so, have evolved to be exceptionally stable. They have evolved to naturally act as ligands for a large variety of receptors and ion channels. These naturally occurring properties also make them ideal for ligand-receptor interactions in drug discovery.
In this study a Targeted-Venom Discovery ArrayGPCR containing 956 venom fractions was screened with the DiscoverX PathHunter® eXpress GPR120S CHO-K1 β-Arrestin GPCR Assay Kits to identify peptides with agonistic effects against GPR120. Luminescent signal was measured using a CLARIOstar+ plate reader (BMG LabTech). Using a mini Z’ on each assay plate we confirmed an acceptable assay robustness (Z’ ≤ 0.697) and identified 24 hit fractions (2.5% hit rate) all from the venom of true cobras. Dose response follow up confirmed the agonistic effects of these hits against GPR120S.

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