Navigation auf zora.uzh.ch

Search ZORA

ZORA (Zurich Open Repository and Archive)

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

Longwell, Chelsea K; Hanna, Stephanie; Hartrampf, Nina; Sperberg, R Andres Parra; Huang, Po-Ssu; Pentelute, Bradley L; Cochran, Jennifer R (2021). Identification of N-Terminally Diversified GLP-1R Agonists Using Saturation Mutagenesis and Chemical Design. ACS Chemical Biology, 16(1):58-66.

Abstract

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

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Scopus Subject Areas:Life Sciences > Biochemistry
Life Sciences > Molecular Medicine
Uncontrolled Keywords:Molecular Medicine, General Medicine, Biochemistry
Language:English
Date:15 January 2021
Deposited On:08 Feb 2023 17:37
Last Modified:29 Oct 2024 02:36
Publisher:American Chemical Society (ACS)
ISSN:1554-8929
OA Status:Closed
Publisher DOI:https://doi.org/10.1021/acschembio.0c00722
PubMed ID:33307682
Project Information:
  • Funder: Novo Nordisk
  • Grant ID:
  • Project Title:
  • Funder: U.S. Department of Commerce
  • Grant ID:
  • Project Title:
  • Funder: Bristol-Myers Squibb
  • Grant ID:
  • Project Title:

Metadata Export

Statistics

Citations

Dimensions.ai Metrics
5 citations in Web of Science®
4 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

0 downloads since deposited on 08 Feb 2023
0 downloads since 12 months

Authors, Affiliations, Collaborations

Similar Publications