Design of novel Xenopus GLP-1-based dual glucagon-like peptide 1 (GLP-1)/glucagon receptor agonists.
Design of novel Xenopus GLP-1-based dual glucagon-like peptide 1 (GLP-1)/glucagon receptor agonists.
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新型爪蟾 GLP-1 双重胰高血糖素样肽 1 (GLP-1)/胰高血糖素受体激动剂的设计。
DOI：
10.1016/j.ejmech.2020.113118
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发表时间：
2020-12
影响因子：
6.7
通讯作者：
Tang Weizhong
中科院分区：
文献类型：
--
作者：
Jiang Neng;Jing Lin;Li Qing;Su Sibiao;Yang Qimeng;Zhou Feng;Chen Xinyu;Han Jing;Tang Chunli;Tang Weizhong
胰高血糖素受体（GCGR）和胰高血糖素样肽1受体（GLP-1 R）的双重激活有可能成为治疗糖尿病和肥胖症的有效疗法。在这里，我们报告了通过合理设计发现的一系列对GLP-1 R和GCGR具有双重活性的肽的发现。基于序列分析，将胃泌酸调节素（OXM）、胰高血糖素或毒蜥外泌肽-4的结构元件工程化到选择性GLP-1 R激动剂非洲爪蟾GLP-1（xGLP-1）中，产生对GLP-1 R和GCGR具有有效双重活性的杂合肽。用脂肪酸进一步修饰产生了一种新的代谢稳定的肽（xGLP/GCG-15），具有增强和平衡的GLP-1 R和GCGR激活。在db/db和饮食诱导的肥胖（DIO）啮齿动物模型中进一步探索了这种先导肽。在相关啮齿动物模型中，长期给予xGLP/GCG-15显著诱导了低血糖效应和体重减轻，改善了葡萄糖耐量，并使脂质代谢、肥胖和肝脏脂肪变性正常化。这些临床前研究表明，xGLP/GCG-15具有开发为新型抗肥胖和/或抗糖尿病候选药物的潜力。考虑到xGLP/GCG-15和临床候选药物MEDI 0382对逆转肝脏脂肪变性的同等作用，它也可能在未来被探索为非酒精性脂肪性肝炎（NASH）的新疗法。
Dual activation of the glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP-1R) has the potential to lead to an effective therapy for the treatment of diabetes and obesity. Here, we report the discovery of a series of peptides with dual activity on GLP-1R and GCGR that were discovered by rational design. Structural elements of oxyntomodulin (OXM), glucagon or exendin-4 were engineered into the selective GLP-1R agonist Xenopus GLP-1 (xGLP-1) on the basis of sequence analysis, resulting in hybrid peptides with potent dual activity at GLP-1R and GCGR. Further modifications with fatty acid resulted in a novel metabolically stable peptide (xGLP/GCG-15) with enhanced and balanced GLP-1R and GCGR activations. This lead peptide was further explored pharmacologically in bothdb/dband diet-induced obesity (DIO) rodent models. Chronic administration of xGLP/GCG-15 significantly induced hypoglycemic effects and body weight loss, improved glucose tolerance, and normalized lipid metabolism, adiposity, and liver steatosis in relevant rodent models. These preclinical studies suggest that xGLP/GCG-15 has potential for development as a novel anti-obesity and/or anti-diabetic candidate. Considering the equal effects of xGLP/GCG-15 and the clinical candidate MEDI0382 on reverse hepatic steatosis, it may also be explored as a new therapy for nonalcoholic steatohepatitis (NASH) in the future.
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影响因子：
7.7
作者：
M. Beaton;S. Guionaud;James Conway;J. Grimsby;C. Rhodes;L. Jermutus;James L. Trevaskis
通讯作者：
M. Beaton;S. Guionaud;James Conway;J. Grimsby;C. Rhodes;L. Jermutus;James L. Trevaskis
DOI：
10.1056/nejmoa1603827
发表时间：
2016-07-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Marso SP;Daniels GH;Brown-Frandsen K;Kristensen P;Mann JF;Nauck MA;Nissen SE;Pocock S;Poulter NR;Ravn LS;Steinberg WM;Stockner M;Zinman B;Bergenstal RM;Buse JB;LEADER Steering Committee;LEADER Trial Investigators
通讯作者：
LEADER Trial Investigators
影响因子：
158.5
作者：
Pi-Sunyer, Xavier;Astrup, Arne;Wilding, John P. H.
通讯作者：
Wilding, John P. H.
影响因子：
5.8
作者：
Kerr, Barry D.;Flatt, Peter R.;Gault, Victor A.
通讯作者：
Gault, Victor A.
影响因子：
168.9
作者：
Ambery, Philip;Parker, Victoria E.;Jermutus, Lutz
通讯作者：
Jermutus, Lutz