Cell-penetrating pepducins targeting the neurotensin receptor type 1 relieve pain.

Pharmacological Research : the Official Journal of the Italian Pharmacological Society
Rebecca L BrouilletteP Sarret

Abstract

Pepducins are cell-penetrating, membrane-tethered lipopeptides designed to target the intracellular region of a G protein-coupled receptor (GPCR) in order to allosterically modulate the receptor's signaling output. In this proof-of-concept study, we explored the pain-relief potential of a pepducin series derived from the first intracellular loop of neurotensin receptor type 1 (NTS1), a class A GPCR that mediates many of the effects of the neurotensin (NT) tridecapeptide, including hypothermia, hypotension and analgesia. We used BRET-based biosensors to determine the pepducins' ability to engage G protein signaling pathways associated with NTS1 activation. We observed partial Gαq and Gα13 activation at a 10 μM concentration, indicating that these pepducins may act as allosteric agonists of NTS1. Additionally, we used surface plasmon resonance (SPR) as a label-free assay to monitor pepducin-induced responses in CHO-K1 cells stably expressing hNTS1. This whole-cell integrated assay enabled us to subdivide our pepducin series into three profile response groups. In order to determine the pepducins' antinociceptive potential, we then screened the series in an acute pain model (tail-flick test) by measuring tail withdrawal latencies t...Continue Reading

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Citations

Oct 10, 2020·Future Medicinal Chemistry·Andy Wai Kan YeungNikolay T Tzvetkov
May 7, 2021·Journal of Medicinal Chemistry·Samuel ObengChristopher R McCurdy
May 12, 2021·Cancer Metastasis Reviews·Élora MidavainePhilippe Sarret

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