New Generation Oxyntomodulin Peptides with Improved Pharmacokinetic Profiles Exhibit Weight Reducing and Anti-Steatotic Properties in Mice.,Bioconjugate Chemistry

当前位置： X-MOL 学术 › Bioconjugate Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

New Generation Oxyntomodulin Peptides with Improved Pharmacokinetic Profiles Exhibit Weight Reducing and Anti-Steatotic Properties in Mice.
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2020-04-03 , DOI: 10.1021/acs.bioconjchem.0c00093
Peng-Yu Yang _{1,

2} , Huafei Zou ₁ , Zaid Amso ₁ , Candy Lee ₁ , David Huang ₁ , Ashley K Woods ₁ , Vân T B Nguyen-Tran ₁ , Peter G Schultz _{1,

2} , Weijun Shen ₁

Affiliation

Oxyntomodulin (OXM) is an intestinal peptide hormone that activates both glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptors. The natural peptide reduces body weight in obese subjects and exhibits direct acute glucoregulatory effects in patients with type II diabetes. However, the clinical utility of OXM is limited due to its lower in vitro potency and short in vivo half-life. To overcome these issues, we developed stapled, long-acting, and highly potent OXM analogs with balanced activities at both GLP-1 and GCG receptors. The lead molecule O14 exhibits potent and long-lasting effects on glucose control, body weight loss, and reduction of hepatic fat reduction in DIO mice. Importantly, O14 significantly reversed hepatic steatosis; reduced liver weight, total cholesterol, and hepatic triglycerides; and improved markers of liver function in a nonalcoholic steatohepatitis (NASH) mouse model. A symmetrical version of the peptide was also shown to be more efficacious and long-lasting in controlling glucose than semaglutide and the clinical candidate cotadutide in wild-type mice, highlighting the utility of our designs of the dual agonist as a potential new therapy for diabetes and liver diseases.

中文翻译：

具有改善的药代动力学特征的新一代催产调节蛋白肽具有减轻小鼠体重和抗脂肪变性的特性。

泌酸调节蛋白（OXM）是一种肠肽激素，可激活胰高血糖素样肽1（GLP-1）和胰高血糖素（GCG）受体。天然肽可减轻肥胖受试者的体重，并在II型糖尿病患者中表现出直接的急性糖调节作用。但是，OXM的临床效用因其较低的体外效价和较短的体内半衰期而受到限制。为了克服这些问题，我们开发了在GLP-1和GCG受体上具有平衡活性的装订，长效且高效的OXM类似物。铅分子O14对DIO小鼠的血糖控制，体重减轻和肝脂肪减少的减少表现出有效而持久的作用。重要的是，O14肝脂肪变性明显逆转；降低肝脏重量，总胆固醇和肝甘油三酸酯；和非酒精性脂肪性肝炎（NASH）小鼠模型中肝功能的改善标志物。在野生型小鼠中，对称形式的该肽在控制葡萄糖方面也显示出比semaglutide和临床候选药物cotadutide更有效，更持久，突显了我们设计的双重激动剂作为糖尿病潜在的新疗法的实用性和肝脏疾病。

更新日期：2020-04-23

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11