Development of Potent Glucagon-like Peptide-1 Agonists with High Enzyme Stability via Introduction of Multiple Lactam Bridges

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.

The Glucose-Dependent Insulinotropic Polypeptide Receptor: A Novel Target for Neuroendocrine Tumor Imaging—First Preclinical Studies

“…Because the truncated peptide GIP(1-30) activates the GIP receptor as efficiently as the fulllength peptide GIP(1-42) (25), the GIP(1-30) was chosen as the peptide motif of our study. The peptide was functionalized with the chelator DOTA via 6-Ahx coupled to the side chains of Lys 16 and Lys 30 , respectively, to obtain EG1, EG2, and EG4. In EG4, the Met 14 was substituted with Nle, as a widely used strategy for stabilizing peptides against oxidative damage and allowing easier handling.…”

“…A new and promising family of G-proteincoupled receptors is the incretin receptor family (8,10,11). The imaging of tumors overexpressing the glucagonlike peptide 1 (GLP-1) receptor was proven to be successful in insulinoma preclinically (12)(13)(14)(15)(16)(17) and clinically (18,19). Recently, it was found that the second member of the incretin receptor family, the glucose-dependent insulinotropic polypeptide (GIP) receptor, is overexpressed in specific NETs.…”

Truncated Glucagon-like Peptide-1 and Exendin-4 α-Conotoxin pl14a Peptide Chimeras Maintain Potency and α-Helicity and Reveal Interactions Vital for cAMP Signaling in Vitro

“…GLP-1 affects receptor binding and signaling (23)(24)(25)(26); however, to date there has been no investigation into the effect of C-terminal truncation of GLP-1 or Ex-4 on peptide helicity nor has there been research into the effect of inducing helicity in truncated analogs on receptor binding and signaling.…”

Stapled Vasoactive Intestinal Peptide (VIP) Derivatives Improve VPAC2 Agonism and Glucose-Dependent Insulin Secretion

“…21 Both techniques are known to stabilize and enhance native α-helicity, which may increase plasma stability and potentially enable in vivo dosing. Both approaches are also likely to increase proteolytic stability by shielding otherwise exposed scissile bonds from the relevant degrading enzymes.…”