...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Journal of Medicinal Chemistry >Exendin 4-Hapten Conjugate Capable of Binding with Endogenous Antibodies for Peptide Half-life Extension and Exerting Long-Acting Hypoglycemic Activity
【24h】

Exendin 4-Hapten Conjugate Capable of Binding with Endogenous Antibodies for Peptide Half-life Extension and Exerting Long-Acting Hypoglycemic Activity

机译：exendin 4-胚珠缀合物能够与肽半衰期延伸的内源性抗体结合，并施加长效的降血糖活性

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Hapten-specific endogenous antibodies are naturally occurring antibodies present in human blood. Herein, we investigated a new strategy in which small-molecule haptens were utilized as naturally occurring antibody binders for peptide half-life extension. The glucagon-like peptide 1 receptor agonist exendin 4 was site-specifically functionalized with the dinitrophenyl (DNP) hapten at the C-terminus via sortase A-mediated ligation. The resulting Ex4-DNP conjugates retained GLP-1 receptor activation potency in vitro and had a similar in vivo acute glucose-lowering effect comparable to that of native Ex4. Pharmacokinetic studies and hypoglycemic duration tests demonstrated that the Ex4-DNP conjugates displayed significantly elongated half-lives and improved long-acting antidiabetic activity in the presence of endogenous anti-DNP antibodies. In chronic treatment studies, once-daily administration of optimal conjugate 7 demonstrated more beneficial effects without prominent toxicity compared with Ex4. This strategy provides a new approach and represents an alternative to the well-established peptide-Fc fusion strategy to improve the peptide half-life and the therapeutic efficacy.
机译：半抗原特异性内源性抗体是存在于人类血液中的天然抗体。在此，我们研究了一种新策略，即利用小分子半抗原作为天然抗体粘合剂延长肽的半衰期。胰高血糖素样肽1受体激动剂exendin 4通过sortase A介导的连接在C端与二硝基苯基（DNP）半抗原进行位点特异性功能化。由此产生的Ex4-DNP结合物在体外保留了GLP-1受体激活效力，并具有与天然Ex4类似的体内急性降糖效果。药代动力学研究和降糖持续时间试验表明，在存在内源性抗DNP抗体的情况下，Ex4-DNP结合物的半衰期显著延长，长效抗糖尿病活性增强。在慢性治疗研究中，与Ex4相比，每日一次服用最佳结合物7显示出更有益的效果，且没有显著的毒性。该策略提供了一种新的方法，并代表了成熟的肽Fc融合策略的替代方案，以提高肽半衰期和治疗效果。

著录项

  • 来源
    《Journal of Medicinal Chemistry》 |2021年第8期|共13页
  • 作者

    Dai Shijie; Hong Haofei; Zhou Kun; Zhao Kai; Xie Yuntian; Li Chen; Shi Jie; Zhou Zhifang; Nie Lei; Wu Zhimeng;

  • 作者单位

    Jiangnan Univ Sch Biotechnol Key Lab Carbohydrate Chem &

    Biotechnol Minist Educ Wuxi 214122 Jiangsu Peoples R China;

    Jiangnan Univ Sch Biotechnol Key Lab Carbohydrate Chem &

    Biotechnol Minist Educ Wuxi 214122 Jiangsu Peoples R China;

    Jiangnan Univ Sch Biotechnol Key Lab Carbohydrate Chem &

    Biotechnol Minist Educ Wuxi 214122 Jiangsu Peoples R China;

    Jiangnan Univ Sch Biotechnol Key Lab Carbohydrate Chem &

    Biotechnol Minist Educ Wuxi 214122 Jiangsu Peoples R China;

    Jiangnan Univ Sch Biotechnol Key Lab Carbohydrate Chem &

    Biotechnol Minist Educ Wuxi 214122 Jiangsu Peoples R China;

    Jiangnan Univ Sch Biotechnol Key Lab Carbohydrate Chem &

    Biotechnol Minist Educ Wuxi 214122 Jiangsu Peoples R China;

    Jiangnan Univ Sch Biotechnol Key Lab Carbohydrate Chem &

    Biotechnol Minist Educ Wuxi 214122 Jiangsu Peoples R China;

    Jiangnan Univ Sch Biotechnol Key Lab Carbohydrate Chem &

    Biotechnol Minist Educ Wuxi 214122 Jiangsu Peoples R China;

    Hisun Biopharmaceut Co Ltd Hangzhou 311404 Zhejiang Peoples R China;

    Jiangnan Univ Sch Biotechnol Key Lab Carbohydrate Chem &

    Biotechnol Minist Educ Wuxi 214122 Jiangsu Peoples R China;

  • 收录信息
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药学;
  • 关键词

相似文献

  • 外文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号