5NIQ

exendin-4 variant with dual GLP-1 / glucagon receptor activity

Summary for 5NIQ

• Entry DOI: 10.2210/pdb5niq/pdb
• NMR Information: BMRB: 34119
• Descriptor: Exendin-4, N-hexadecanoyl-L-glutamic acid (2 entities in total)
• Functional Keywords: exendin-4 analogue, dual glp-1 / glucagon agonist, hormone
• Biological source: Heloderma suspectum (Gila monster)
• Total number of polymer chains: 1
• Total formula weight: 4605.10

Authors

Evers, A.,Kurz, M. (deposition date: 2017-03-24, release date: 2018-02-28, Last modification date: 2024-10-23)

Primary citation

Evers, A.,Haack, T.,Lorenz, M.,Bossart, M.,Elvert, R.,Henkel, B.,Stengelin, S.,Kurz, M.,Glien, M.,Dudda, A.,Lorenz, K.,Kadereit, D.,Wagner, M.
Design of Novel Exendin-Based Dual Glucagon-like Peptide 1 (GLP-1)/Glucagon Receptor Agonists.
J.Med.Chem., 60:4293-4303, 2017

PubMed Abstract: Dual activation of the glucagon-like peptide 1 (GLP-1) and glucagon receptor has the potential to lead to a novel therapy principle for the treatment of diabesity. Here, we report a series of novel peptides with dual activity on these receptors that were discovered by rational design. On the basis of sequence analysis and structure-based design, structural elements of glucagon were engineered into the selective GLP-1 receptor agonist exendin-4, resulting in hybrid peptides with potent dual GLP-1/glucagon receptor activity. Detailed structure-activity relationship data are shown. Further modifications with unnatural and modified amino acids resulted in novel metabolically stable peptides that demonstrated a significant dose-dependent decrease in blood glucose in chronic studies in diabetic db/db mice and reduced body weight in diet-induced obese (DIO) mice. Structural analysis by NMR spectroscopy confirmed that the peptides maintain an exendin-4-like structure with its characteristic tryptophan-cage fold motif that is responsible for favorable chemical and physical stability.

PubMed: 28448133
DOI: 10.1021/acs.jmedchem.7b00174

Experimental method

SOLUTION NMR