6GDZ
exendin-4 based dual GLP-1/glucagon receptor agonist
Summary for 6GDZ
| Entry DOI | 10.2210/pdb6gdz/pdb |
| NMR Information | BMRB: 34264 |
| Descriptor | Exendin-4, (2~{S})-2-[[(4~{S})-4-(hexadecanoylamino)-5-oxidanyl-5-oxidanylidene-pentanoyl]amino]pentanedioic acid (2 entities in total) |
| Functional Keywords | hormone |
| Biological source | Heloderma suspectum (Gila monster) |
| Total number of polymer chains | 1 |
| Total formula weight | 4657.24 |
| Authors | |
| Primary citation | Evers, A.,Bossart, M.,Pfeiffer-Marek, S.,Elvert, R.,Schreuder, H.,Kurz, M.,Stengelin, S.,Lorenz, M.,Herling, A.,Konkar, A.,Lukasczyk, U.,Pfenninger, A.,Lorenz, K.,Haack, T.,Kadereit, D.,Wagner, M. Dual Glucagon-like Peptide 1 (GLP-1)/Glucagon Receptor Agonists Specifically Optimized for Multidose Formulations. J. Med. Chem., 61:5580-5593, 2018 Cited by PubMed Abstract: Novel peptidic dual agonists of the glucagon-like peptide 1 (GLP-1) and glucagon receptor are reported to have enhanced efficacy over pure GLP-1 receptor agonists with regard to treatment of obesity and diabetes. We describe novel exendin-4 based dual agonists designed with an activity ratio favoring the GLP-1 versus the glucagon receptor. As result of an iterative optimization procedure that included molecular modeling, structural biological studies (X-ray, NMR), peptide design and synthesis, experimental activity, and solubility profiling, a candidate molecule was identified. Novel SAR points are reported that allowed us to fine-tune the desired receptor activity ratio and increased solubility in the presence of antimicrobial preservatives, findings that can be of general applicability for any peptide discovery project. The peptide was evaluated in chronic in vivo studies in obese diabetic monkeys as translational model for the human situation and demonstrated favorable blood glucose and body weight lowering effects. PubMed: 29879354DOI: 10.1021/acs.jmedchem.8b00292 PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
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