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06 19, 2020;15 (6): 1340-1348.

Hydrocarbon-Stitched Peptide Agonists of Glucagon-Like Peptide-1 Receptor.

Gregory H Bird, Accalia Fu, Silvia Escudero, Marina Godes, Kwadwo Opoku-Nsiah, Thomas E Wales, Michael D Cameron, John R Engen, Nika N Danial, Loren D Walensky
Author Information
  1. Gregory H Bird: Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, United States.
  2. Accalia Fu: Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston Massachusetts 02215, United States.
  3. Silvia Escudero: Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, United States.
  4. Marina Godes: Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, United States.
  5. Kwadwo Opoku-Nsiah: Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, United States.
  6. Thomas E Wales: Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115, United States.
  7. Michael D Cameron: DMPK Core, Department of Molecular Medicine, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States.
  8. John R Engen: Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115, United States.
  9. Nika N Danial: Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston Massachusetts 02215, United States.
  10. Loren D Walensky: Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, United States. ORCID
PMID: 32348108 DOI: 10.1021/acschembio.0c00308

Abstract

Glucagon-like peptide 1 (GLP-1) is a natural peptide agonist of the GLP-1 receptor (GLP-1R) found on pancreatic β-cells. Engagement of the receptor stimulates insulin release in a glucose-dependent fashion and increases β-cell mass, two ideal features for pharmacologic management of type 2 diabetes. Thus, intensive efforts have focused on developing GLP-1-based peptide agonists of GLP-1R for therapeutic application. A primary challenge has been the naturally short half-life of GLP-1 due to its rapid proteolytic degradation . Whereas mutagenesis and lipidation strategies have yielded clinical agents, we developed an alternative approach to preserving the structure and function of GLP-1 by all-hydrocarbon , + 7 stitching. This particular "stitch" is especially well-suited for reinforcing and protecting the structural fidelity of GLP-1. Lead constructs demonstrate striking proteolytic stability and potent biological activity . Thus, we report a facile approach to generating alternative GLP-1R agonists for glycemic control.

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Grants

  1. R01 DK078081/NIDDK NIH HHS
  2. R35 CA197583/NCI NIH HHS
  3. R50 CA211399/NCI NIH HHS

MeSH Term

Animals
Cell Line
Drug Discovery
Glucagon-Like Peptide 1
Glucagon-Like Peptide-1 Receptor
Humans
Male
Mice
Molecular Docking Simulation
Peptides

Chemicals

Glucagon-Like Peptide-1 Receptor
Peptides
Glucagon-Like Peptide 1
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't
Article has an altmetric score of 10

Word Cloud

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