GLP-1R
June 2022
Glucagon peptide-like receptor
Glucagon peptide-like receptor (GLP-1R) belongs to the class B G-protein-coupled receptors (GPCR) which are major targets for the treatment of diabetes, obesity, and nonalcoholic steatohepatitis (NASH). The existing GLP-1R agonists are almost all peptides that require parenteral administration.
Last month, FDA has approved a new peptide drug with dual targeting called Mounjaro (tirzepatide) which has shown increased efficacy in controlling blood sugar than other diabetes therapies.
However, peptides cause unpleasant gastrointestinal side effects and are expensive to manufacture which limits their usage. Scientists are working on developing more non-peptide agonists and significant progress has been made with a couple of small molecules that are now undergoing clinical trials, including Pfizer’s PF 06882961 (danuglipron) and Chugai/Eli Lilly’s LY3502970 (OWL833). But little has been known about their activity, binding mode, and signaling, therefore, scientists from industry and academia conducted pharmacological studies on the two molecules and the natural agonist of GLP-1 receptor (GLP1 peptide).
Structural insights from the resolved cryo-EM structures contribute to the understanding of comparable pharmacological profiles between PF 06882961 and GLP-1, but not CHU-128 (another non-peptide agonist from the Chugai patent series) and could contribute to the structure-based drug design of non-peptide drugs for GLP-1R.
Scientists observed that PF 06882961 binds to the transmembrane (TM) binding pocket very similarly to the native peptide. Even though the ligand is smaller and does not reach the base of the pocket as the native peptide, its polar network continuously extends to the bottom due to the presence of structural water molecules, overlapping the interaction pattern of GLP-1 peptide (Image 1).
Image 1: The water-mediated polar network of Pfizer’s ligand (PF 06882961) with similar interactions with the target as its native ligand GLP-1 (PDB structure: 6X1A)
The image was done with 3decision - a protein structure repository that allows you to easily visualize electron density maps in the 3D viewer.
In contrast, CHU-128 displays a different mechanism of action which could be explained by a difference in the binding mode to the receptor. Instead of entering the TM binding site, the CHU-128 binds on the superficial part of the pocket, with polar interactions very similar to the ones observed in PF and GLP-1. However, the ligand is unable to form rigid interactions within the buried pocket. This induces an open conformation of the TM binding site, which causes bulk water molecules to easily enter and exit the pocket. Their higher mobility thus prevents the ligand to form an extensive polar network covering the whole binding site.
This “water movement” phenomenon is also seen on the cryoEM map of receptor-CHU-128 structure (PDB structure: 6X19) as a weakly resolved electron density (even if the overall resolution of the structure is better than the one of GLP1R with PF 06882961) (Image 2).
Image 2: The absence of water network in GLP-1R structure with CHU-128 compared to the one with PF 06882961 (PDB structure:6X19). The open conformation causes the increased transport of water molecules which is confirmed with the weak density on the cryoEM map.
The structural differences among water-mediated polar patterns can be the explanation for the diversity among pharmacological responses observed upon binding of the two different ligands to the GLP-1 receptor. The structural insights pave the way for structure-based drug design of efficient non-peptide drugs for GLP-1R.