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Updated: Jun 10, 2026

The Use of a β-lactamase-based Conductimetric Biosensor Assay to Detect Biomolecular Interactions
Published on: February 1, 2018
Development of potent glucagon-like peptide-1 agonists with high enzyme stability via introduction of multiple lactam
Eunice N Murage1, Guangzu Gao, Alessandro Bisello
1Department of Chemistry, University of Texas at Dallas, Richardson, Texas 75080,USA.
Abstract:
Glucagon-like peptide-1 (GLP-1) has the ability to lower the blood glucose level, and its regulatory functions make it an attractive therapeutic agent for the treatment of type 2 diabetes. However, its rapid degradation by enzymes like dipeptidyl peptidase-IV (DPP-IV) and neutral endopeptidase (NEP) 24.11 severely compromises its effective clinical use. Whereas specific DPP-IV inhibitors have been developed, NEP 24.11 targets multiple sites in the GLP-1 sequence, which makes it difficult to block. To address this drawback, we have designed and synthesized conformationally constrained GLP-1 analogues by introducing multiple lactam bridges that stabilized both alpha-helices in the N- and C-terminal regions simultaneously. In addition to improving the receptor activation capability (up to 5-fold) by fixing the alpha-helical conformations required for optimal receptor interaction, the introduced lactam bridges provided outstanding shielding over NEP 24.11 (half-life of >96 h). These highly constrained peptides are the first examples of NEP 24.11-resistant GLP-1 analogues.
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