Insightful Backbone Modifications Preventing Proteolytic Degradation of Neurotensin Analogs Improve NTS1-Induced Protective Hypothermia. IF(2019) 4,204

Santo Previti, Melanie Vivancoe, Emmanuelle Remand, Sabrina Beaulieu, Jean-Michel Longpre, Steven Ballet, Philippe Sarret, Florine Cavelier

Onderzoeksoutput: Articlepeer review

6 Citaten (Scopus)


Therapeutic hypothermia represents a brain-protective strategy for multiple emergency situations, such as stroke or traumatic injury. Neurotensin (NT), which exerts its effects through activation of two G protein-coupled receptors, namely NTS1 and NTS2, induces a strong and long-lasting decrease in core body temperature after its central administration. Growing evidence demonstrates that NTS1 is the receptor subtype mediating the hypothermic action of NT. As such, potent NTS1 agonists designed on the basis of the minimal C-terminal NT(8-13) bioactive fragment have been shown to produce mild hypothermia and exert neuroprotective effects under various clinically relevant conditions. The high susceptibility of NT(8-13) to protease degradation (half-life <2 min) represents, however, a serious limitation for its use in pharmacological therapy. In light of this, we report here a structure-activity relationship study in which pairs of NT(8-13) analogs have been developed, based on the incorporation of a reduced Lys 8-Lys 9 bond. To further stabilize the peptide bonds, a panel of backbone modifications was also inserted along the peptide sequence, including Sip 10, D-Trp 11, Dmt 11, Tle 12, and TMSAla 13. Our results revealed that the combination of appropriate chemical modifications leads to compounds exhibiting improved resistance to proteolytic cleavages (>24 h; 16). Among them, the NT(8-13) analogs harboring the reduced amine bond combined with the unnatural amino acids TMSAla 13 (4) and Sip 10 (6) or the di-substitution Lys 11 - TMSAla 13 (12), D-Trp 11-TMSAla 13 (14), and Dmt 11-Tle 12 (16) produced sustained hypothermic effects (−3°C for at least 1 h). Importantly, we observed that hypothermia was mainly driven by the increased stability of the NT(8-13) derivatives, instead of the high binding-affinity at NTS1. Altogether, these results reveal the importance of the reduced amine bond in optimizing the metabolic properties of the NT(8-13) peptide and support the development of stable NTS1 agonists as first drug candidate in neuroprotective hypothermia.

Originele taal-2English
Pagina's (van-tot)406
TijdschriftFrontiers in Chemistry
StatusPublished - 5 jun 2020

Bibliografische nota

Funding Information:
The authors thank Pr Éric Marsault for allowing them to use the UPLC/MS instrument for plasma stability assays. Funding. This work was supported by the Canadian Institute of Health Research (CIHR) (FDN-148413) awarded to PS and by France Life Imaging (Grant No. ANR-11-INBS-0006 - SP.) from the French program Investissements d'Avenir to FC and MV was supported by a research fellowship from the Institut de Pharmacologie de Sherbrooke (IPS) and Centre d′Excellence en Neurosciences de l′Université de Sherbrooke (CNS). PS holds a Canada Research Chair in Neurophysiopharmacology of Chronic Pain.

Publisher Copyright:
© Copyright © 2020 Previti, Vivancos, Rémond, Beaulieu, Longpré, Ballet, Sarret and Cavelier.

Copyright 2020 Elsevier B.V., All rights reserved.

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