In Search of the Optimal Macrocyclization Site for Neurotensin

ACS Med Chem Lett. 2018 Jan 29;9(3):227-232. doi: 10.1021/acsmedchemlett.7b00500. eCollection 2018 Mar 8.


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.