Conditional and Reversible Activation of Class A and B G Protein-Coupled Receptors Using Tethered Pharmacology.

ABSTRACT: Understanding the activation and internalization of G protein-coupled receptors (GPCRs) using conditional approaches is paramount to developing new therapeutic strategies. Here, we describe the design, synthesis, and testing of ExONatide, a benzylguanine-linked peptide agonist of the glucagon-like peptide-1 receptor (GLP-1R), a class B GPCR required for maintenance of glucose levels in humans. ExONatide covalently binds to SNAP-tagged GLP-1R-expressing cells, leading to prolonged cAMP generation, Ca²⁺ rises, and intracellular retention of the receptor. These effects were readily switched OFF following cleavage of the introduced disulfide bridge using the cell-permeable reducing agent beta-mercaptoethanol (BME). A similar approach could be extended to a class

SUBMITTER: Podewin T 

PROVIDER: S-EPMC5832994 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature