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In Search of the Optimal Macrocyclization Site for Neurotensin
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-01-29 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00500
Marc Sousbie 1 , Élie Besserer-Offroy 1 , Rebecca L. Brouillette 1 , Jean-Michel Longpré 1 , Richard Leduc 1 , Philippe Sarret 1 , Éric Marsault 1
Affiliation  

Neurotensin exerts potent analgesic effects following activation of its cognate GPCRs. In this study, we describe a systematic exploration, using structure-based design, of conformationally constraining neurotensin (8–13) with the help of macrocyclization and the resulting impacts on binding affinity, signaling, and proteolytic stability. This exploratory study led to a macrocyclic scaffold with submicromolar binding affinity, agonist activity, and greatly improved plasma stability.

中文翻译:

寻找神经降压素的最佳大环化位点

激活其相关的GPCR后,神经降压素发挥有效的镇痛作用。在这项研究中,我们描述了基于结构设计的系统探索,借助大环化对构象约束神经降压素(8-13)及其对结合亲和力,信号传导和蛋白水解稳定性的影响。这项探索性研究导致了具有亚微摩尔结合亲和力,激动剂活性并大大改善了血浆稳定性的大环支架。
更新日期:2018-01-29
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