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Published on: November 17, 2023
In Search of the Optimal Macrocyclization Site for Neurotensin
Marc Sousbie1, Élie Besserer-Offroy1, Rebecca L Brouillette1
1Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e Avenue Nord, Sherbrooke, Quebec J1H 5N4, Canada.
Abstract:
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.
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