Back to Technologies Available for Partnering

Stitched GLP-1 Peptides for Diabetes, Weight Loss, and Other Metabolic and Non-Metabolic Diseases

Hydrocarbon-stitched GLP-1R agonists demonstrate enhanced proteolytic stability and functional activity, providing an alternative drug composition for clinical application.

  • Therapeutics

Project Overview

  • Glucagon-like peptide-1 (GLP-1) plays a pivotal role in regulating glucose homeostasis through its action on GLP-1 receptors (GLP-1R) located on pancreatic β-cells. Activation of these receptors enhances insulin secretion in a glucose-dependent manner, inhibits glucagon release, and delays gastric emptying, thereby effectively reducing blood glucose levels.
  • Glucagon-like peptide-1 receptors (GLP-1R) agonists are cornerstone in the treatment of type 2 diabetes mellitus (T2DM) and obesity and under investigation for a range of other conditions.
  • Researchers at Dana-Farber have developed an innovative approach to GLP-1R agonist design using hydrocarbon-stitching technology. Unlike traditional stabilization strategies that may compromise bioavailability and manufacture, the stitched peptides both optimize peptide stability, GLP-1R interaction, and biological activity.
  • These stitched GLP-1R agonists are available for licensing.

Technology

Glucagon-like peptide-1 (GLP-1) plays a pivotal role in regulating glucose homeostasis through its action on GLP-1 receptors (GLP-1R) located on pancreatic β-cells. Activation of these receptors enhances insulin secretion in a glucose-dependent manner, inhibits glucagon release, and delays gastric emptying, thereby effectively reducing blood glucose levels. These properties have made GLP-1R agonists a cornerstone in the treatment of type 2 diabetes mellitus (T2DM) and obesity, with drugs like semaglutide and tirzepatide demonstrating significant therapeutic efficacy.

Despite their success, current GLP-1R agonists face challenges, motivating the search for novel GLP-1 based therapies. Native GLP-1 is rapidly degraded by proteolytic enzymes, necessitating stabilization strategies to extend its half-life. While substitutions at proteolysis-prone sites and modifications such as lipidation or PEGylation have substantially improved peptide stability, they often introduce trade-offs, including steric hindrance and associated reduced receptor binding affinity and challenges in synthesis and production. These limitations motivate the search for novel approaches to enhance both the pharmacokinetic and pharmacodynamic profiles and manufacturing of GLP-1-based therapies.

The Walensky Lab at Dana-Farber has pioneered an innovative approach to GLP-1R agonist design using hydrocarbon-stitching technology. This method involves introducing all-hydrocarbon cross-links into the peptide structure at strategic positions to reinforce its native α-helical conformation. These stitches provide markedly enhanced proteolytic resistance while maintaining receptor-binding integrity. Unlike traditional stabilization strategies that may compromise bioavailability and manufacture, the stitched peptides both optimize peptide stability, GLP-1R interaction, and biological activity.

Experimental results underscore the promise of this technology. Stitched GLP-1 analogs exhibit a 24-fold increase in proteolytic half-life compared to native GLP-1 and outperform semaglutide by a factor of two in vitro. In vivo studies further validate these findings, showing superior glucose-lowering effects in hyperglycemic mice, characterized by more rapid and sustained glucose clearance. This dual improvement in stability and activity positions stitched GLP-1 agonists as a compelling alternative to current GLP-1 therapeutics, with the potential to achieve distinct and improved clinical outcomes across a range of metabolic and non-metabolic diseases.

The Walensky Lab’s hydrocarbon-stitched GLP-1R agonists outperform established drugs, including semaglutide, in proteolytic half-life and rate of glucose clearance.

Team Members: Loren Walensky, MD, PhD, Gregory Bird, PhD

Applications

These novel GLP1R agonists have therapeutic potential in:

  • Type II diabetes
  • Obesity.
  • Cardiovascular risk reduction.
  • Chronic kidney disease.
  • Non-alcoholic fatty liver disease.
  • Polycystic ovary syndrome.
  • Neuroprotection, including in Alzheimer’s and Huntington’s diseases.

Interested in learning more?

Walensky et al. Hydrocarbon-Stitched Peptide Agonists of Glucagon-Like Peptide-1 Receptor. 

ACS Chemical Biology paper

Opportunities

Dana-Farber Cancer Institute is looking for the right partner with an interest in licensing these assets for further development as a therapeutic to benefit patients.

Get in touch

Team Members