| Structural highlights
Function
[EXE4_HELSU] Venom protein that mimics the incretin hormone glucagon-like peptide 1 (GLP-1). It stimulates insulin synthesis and secretion, protects against beta-cell apoptosis in response to different insults, and promotes beta-cell proliferation. It also promotes satiety, reduces food intake, reduces fat deposition, reduces body weight and inhibits gastric emptying. Interacts with GLP-1 receptor (GLP1R). Induces hypotension that is mediated by relaxation of cardiac smooth muscle.[1] [2]
Publication Abstract from PubMed
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 & synthesis, experimental activity and solubility profiling, a candidate molecule was identified. Novel SAR points are reported that allowed to fine-tune the desired receptor activity ratio and increased solubility in the presence of antimicrobial preservatives - findings which 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.
Dual Glucagon-like Peptide 1 (GLP-1)/Glucagon Receptor Agonists Specifically Optimized for Multi-dose Formulations.,Evers A, Bossart M, Pfeiffer-Marek S, Elvert R, Schreuder HA, Kurz M, Stengelin S, Lorenz M, Herling A, Konkar AA, Lukasczyk U, Pfenninger A, Lorenz K, Haack T, Kadereit D, Wagner M J Med Chem. 2018 Jun 7. doi: 10.1021/acs.jmedchem.8b00292. PMID:29879354[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Thorens B, Porret A, Buhler L, Deng SP, Morel P, Widmann C. Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor. Diabetes. 1993 Nov;42(11):1678-82. PMID:8405712
- ↑ Fry BG, Roelants K, Winter K, Hodgson WC, Griesman L, Kwok HF, Scanlon D, Karas J, Shaw C, Wong L, Norman JA. Novel venom proteins produced by differential domain-expression strategies in beaded lizards and gila monsters (genus Heloderma). Mol Biol Evol. 2010 Feb;27(2):395-407. doi: 10.1093/molbev/msp251. Epub 2009 Oct , 15. PMID:19837656 doi:http://dx.doi.org/10.1093/molbev/msp251
- ↑ Evers A, Bossart M, Pfeiffer-Marek S, Elvert R, Schreuder HA, Kurz M, Stengelin S, Lorenz M, Herling A, Konkar AA, 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 Multi-dose Formulations. J Med Chem. 2018 Jun 7. doi: 10.1021/acs.jmedchem.8b00292. PMID:29879354 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b00292
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