Development of next-generation allosteric compounds for the GLP-1R based on human receptor variants to treat type 2 diabetes – alloGLP1R

The glucagon-like-peptide-1 receptor (GLP-1R), a class B G protein-coupled receptor (GPCR), is a well-validated target for the treatment of type 2 diabetes mellitus (T2DM) with several peptide agonists on the market. These drugs improve glycemic control and reduce body weight but suffer also from side effects such as nausea and vomiting and require parenteral administration reducing patient adherence of this in life-long therapy. Small molecules that act as GLP-1R allosteric modulators emerged recently as a promising alternative. We propose here to identify functionally relevant allosteric binding sites at the GLP-1R based on natural GLP-1R variants, to identify binders at this site by virtual screening and to characterize their functional properties.