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In Search of the Optimal Macrocyclization Site for Neurotensin.

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.

SUBMITTER: Sousbie M

PROVIDER: S-EPMC5846049 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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In Search of the Optimal Macrocyclization Site for Neurotensin.

Sousbie Marc M Besserer-Offroy Élie É Brouillette Rebecca L RL Longpré Jean-Michel JM Leduc Richard R Sarret Philippe P Marsault Éric É

ACS medicinal chemistry letters 20180129 3

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. ...[more]

PMID: 29541365

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