Unlocking the hidden potential of the orphan receptor GPR85 as a novel therapeutic target: Finding lead compounds, structure-activity relationship study and pharmacological evaluation

• Applicant: Dr. Thanigaimalai Pillaiyar
• Subject Area: Pharmacy ; Pharmacology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 550034729

The goal of this project is to elucidate the function and pharmacology of GPR85 with potent agonists that are metabolically stable, soluble, and non-toxic. To achieve this goal, the following specific aims will be pursued: 1. Identification and optimization of potent GPR85 agonists. Building on our recent breakthrough discovery of surrogate ligands for GPR85, we will optimize our active scaffolds through medicinal chemistry efforts guided by SAR studies to improve their potency, selectivity, and drug-like properties. The resulting agonists should be highly selective (>2 log units) versus other SREBs, possess solubility and metabolic stability, and display further properties suitable for in vitro and in vivo applications. To facilitate the pharmacological characterization of the receptor, a tritiated version of the best compounds will also be generated. 2. Investigation of the molecular interactions between the GPR85 agonists and the receptor. The binding of our ligand on the receptor will be verified through binding experiment with tritiated compounds. In addition, the molecular interactions of the GPR85 agonists with the receptor will be studied using molecular modelling supported by the GPR85 homology model based on GPCR crystal structures as templates. The model, in particular the predicted binding pocket, will be validated by targeted mutagenesis. 3. Dissection of GPR85 signalling pathways and cellular consequences of activation. The most potent and efficacious agonists developed in Aims 1 and 2 will be utilized as tools to explore the downstream signaling pathways of GPR85 and define the cellular consequences of its activation, when it is heterologously expressed in HEK293 cells and in cells where GPR85 is present at physiological levels such as hippocampal neurons. The signaling pathways will be dissected through a combination of biochemical assays, cellular imaging, and gene expression analyses. Ultimately, the best candidates will be injected in mice and standard behavioral assessment conducted. Overall, this research project will enhance our understanding of GPR85 and provide a foundation for the development of new therapeutics targeting this receptor. The tools developed in this project will be used to dissect precisely the GPR85 signaling pathways and define the cellular consequences of its activation in a physiological context (such as hippocampal neurons).

• DFG Programme: Research Grants
• International Connection: Belgium
• Partner Organisation: Fonds National de la Recherche Scientifique - FNRS
• Cooperation Partner: Professor Julien Hanson, Ph.D.