Modifying a Hydroxyl Patch in Glucagon-like Peptide 1 Produces Biased Agonists with Unique Signaling Profiles

P Wang, TA Hill, J Mitchell, RL Fitzsimmons, W Xu, Z Loh, JY Suen, J Lim, A Iyer, and DP Fairlie J. Med. Chem. DOI 10.1021/acs.jmedchem.2c00653

Abstract: Glucagon-like peptide-1 (GLP-1) lowers blood glucose by inducing insulin but also has other poorly understood properties. Here, we show that hydroxy amino acids (Thr11, Ser14, Ser17, Ser18) in GLP-1(7–36) act in concert to direct cell signaling. Mutating any single residue to alanine removes one hydroxyl group, thereby reducing receptor affinity and cAMP 10-fold, with Ala11 or Ala14 also reducing β-arrestin-2 10-fold, while Ala17 or Ala18 also increases ERK1/2 phosphorylation 5-fold.