Biology subjects

Longpre, J.-M.

Publications and source records attributed to Longpre, J.-M..

3 recordsLinked to original sources

bioRxiv2025

A neurotensin receptor type 1-derived pepducin acts as a biased allosteric modulator to regulate target receptor function

Pepducins are synthetic membrane-tethered lipopeptides designed to allosterically modulate G protein-coupled receptor (GPCR) signaling. Here, we characterize a series of pepducins targeting the neurotensin receptor type 1 (NTS1), revealing multifaceted modulation of this receptor class. Using BRET-based biosensors, we show that PP-001, a pepducin derived from NTS1s first intracellular loop, preferentially activates G protein over {beta}-arrestin signaling while inhibiting NT binding, NT-induced {beta}-arrestin recruitment, and NTS1 receptor internalization, thereby acting as biased allosteric agonist and negative allosteric modulator. PP-001 also promotes the formation of both homo- and heteromeric multi-receptor units. In vivo, PP-001 elicits potent, sustained hypotensive effects, reversible by the NTS1 antagonist SR48692. Finally, although the mechanism of pepducin-receptor interaction remains unclear, this study identifies a critical N-terminal RKK motif for PP-001s biological activity. Thermodenaturation assays with purified NTS1 and mutagenesis further provide evidence for the role of NTS1s H8 domain in direct pepducin-receptor interaction. This work highlights pepducins modulatory potential as pharmacological tools for GPCR-targeted drug development.

pharmacology and toxicology↗

bioRxiv2024

CCR2 silencing in sensory neurons blocks bone cancer progression

The peripheral nervous system contributes to cancer growth, in part by shaping the immunological niche of the tumor. How the nervous system influences bone cancer progression, and whether the underlying neuroimmune pathways can be targeted therapeutically, remain unclear. Here we demonstrate a profound influence of the peripheral nervous system on tumor progression that can be countered by silencing chemokine receptor signaling in sensory neurons. Axotomy of the tumor-innervating femoral nerve inhibits tumor progression in animals bearing bone cancer, whereas intrathecal delivery of the tumor-associated proinflammatory chemokine CCL2 promotes both tumor growth and allodynia. Silencing CCR2 in dorsal root ganglion (DRG) neurons with a newly developed lipid nanoparticle-formulated Dicer-substrate siRNA impedes tumor progression and pathological bone remodeling, and relieves bone cancer-associated pain. Mechanistically, bone cancer drives CCR2-dependent transport of substance P and CGRP along the tumor-innervating femoral nerve, and these neuropeptides expand the tumor-associated macrophage population; silencing CCR2 in DRG neurons normalizes the neuropeptide milieu and ameliorates altered bone remodeling. We thus define a targetable neuroimmune axis that contributes to cancer progression. HighlightsO_LICancer progression activates sensory neurons, driving pain hypersensitivity and neuropeptide release. C_LIO_LIAxotomy of the tumor-innervating femoral nerve impedes tumor progression. C_LIO_LICCL2-CCR2 signaling in DRG neurons promotes pain hypersensitivity and cancer growth. C_LIO_LISilencing CCR2 in the DRG reduces pain hypersensitivity, tumor-associated macrophage numbers and cancer growth. C_LI

neuroscience↗

bioRxiv2023

CCR2-targeting pepducins reduce T cell-nociceptor interaction driving bone cancer pain

Inhibition of the CCL2/CCR2 chemokine signaling represents a promising avenue for the development of non-opioid pain treatment, particularly for painful bone metastases. To investigate the involvement of CCR2 in cancer-induced bone pain, we generated and characterized the functional activities of a novel cell-penetrating pepducin, namely PP101, acting as an intracellular negative allosteric modulator of CCR2. In vivo, PP101 was effective in relieving neuropathic and bone cancer pain. By targeting CCR2, PP101 reduced bone cancer pain by preventing infiltration of CD4+ and CD8+ T cells and by decreasing the neuroimmune communication network within the dorsal root ganglia. Importantly, reduced neuroinflammatory milieu in the dorsal root ganglia induced by PP101 did not result in deleterious tumor progression or behavioral adverse effects. Thus, targeting the neuroimmune crosstalk through allosteric inhibition of CCR2 may represent an effective and safe avenue for the management of bone cancer pain. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/556569v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@15c2d43org.highwire.dtl.DTLVardef@9fa40corg.highwire.dtl.DTLVardef@cb457dorg.highwire.dtl.DTLVardef@13f36e1_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIBreast cancer bone metastases induce pain by activating CCR2 on sensory neurons. C_LIO_LIDRG-infiltrating CD4+ and CD8+ T cells promote the development of bone cancer pain. C_LIO_LICCR2 inhibition by PP101 suppresses DRG neuroinflammation and neuronal excitability. C_LIO_LIPP101 alleviates bone cancer pain without behavioral or physiological side effects. C_LI

neuroscience↗