Identification of N-Terminally Diversified GLP-1R Agonists Using Saturation Mutagenesis and Chemical Design

• DOI: 10.1021/acschembio.0c00722
• Publication Date: 2020-12-14T13:00:38Z
• Authors: Chelsea K. Longwell; Stephanie Hanna; Nina Hartrampf; R. Andres Parra S...; Po-Ssu Huang; Bradley L. Pentelute; Jennifer R. Cochran
• Keywords: Saturated mutagenesis; Identification; Chemical Biology

The glucagon-like peptide 1 receptor (GLP-1R) is a class B G-protein coupled (GPCR) and diabetes drug target expressed mainly in pancreatic β-cells that, when activated by its agonist (GLP-1) after meal, stimulates insulin secretion β-cell survival proliferation. N-terminal region of GLP-1 interacts with membrane-proximal residues GLP-1R, stabilizing active conformation to trigger intracellular signaling. best-studied peptides, exendin-4, share sequence homology at their region; however, modifications that can be tolerated here are not fully understood. In this work, functional screen variants randomized domains reveals new GLP-1R agonists uncovers pattern whereby negative charge preferred the third position various contexts. We further tested sequence–structure–activity principle synthesizing analogues where was mutated both canonical noncanonical amino acids. discovered highly analogue which native glutamate residue three positions from N-terminus replaced sulfo-containing acid cysteic (GLP-1-CYA). binding downstream signaling properties elicited GLP-1-CYA were similar wild type peptide. Computational modeling identified likely mode interaction negatively charged side chain an arginine on GLP-1R. This work highlights strategy combinatorial screening chemical exploration could used generate novel for other receptors ligands.