6GE2

exendin-4 based dual GLP-1/glucagon receptor agonist

6GE2 の概要

• エントリーDOI: 10.2210/pdb6ge2/pdb
• NMR情報: BMRB: 34266
• 分子名称: Exendin-4, (2~{S})-2-[[(4~{S})-4-(hexadecanoylamino)-5-oxidanyl-5-oxidanylidene-pentanoyl]amino]pentanedioic acid (2 entities in total)
• 機能のキーワード: hormone
• 由来する生物種: Heloderma suspectum (Gila monster)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 4795.53

構造登録者

Evers, A.,Kurz, M. (登録日: 2018-04-25, 公開日: 2018-06-20, 最終更新日: 2025-04-09)

主引用文献

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

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: 29879354
DOI: 10.1021/acs.jmedchem.8b00292

実験手法

SOLUTION NMR