Antinociception and neuroprotection of the peptidic G protein-coupled estrogen receptor inverse agonist PLMI in the murine model of paclitaxel-induced peripheral neuropathy Baptiste Jouffre, Alexandre Acramel, Pascale Coric, Pauline Gousseau, Julie Barbier, et al. British Journal of Pharmacology, 2026 Background and Purpose The G protein‐coupled estrogen receptor (GPER) participates in nociception. The GPER inverse agonist, a tetrapeptide (PLMI), was studied on pain‐like symptoms, in murine models of chemotherapy‐induced peripheral neuropathy. Experimental Approach All experiments were performed in mice. We used the PLMI and the GPER antagonist G15 to study the role of GPER in mechanical allodynia in the model of paclitaxel‐induced peripheral neuropathy. Sites of GPER/PLMI actions were explored by using nociceptors and dorsal horn GPER knockouts. The effect of PLMI and/or G15 was assessed in dorsal root ganglia primary cultures to explore the role of GPER in neuronal calcium flux. After a chronic administration of PLMI, the antinociceptive and neuroprotective effects were investigated in the paclitaxel‐induced neuropathy model. Short term memory, reward‐related conditioning and acute effects in bortezomib‐ and oxaliplatin‐induced nociception were evaluated. NMR and CD spectroscopy were used to determine the conformation of the peptide PLMI, in solution. Key Results In our paclitaxel‐induced pain‐like symptoms model, peripheral, spinal and supraspinal GPER participates in nociception. The peptide PLMI decreases nociception by lowering intraneuronal free calcium flux. Chronic PLMI treatment reduces pain‐like behaviours and protects against nerve conduction velocity deficits, without causing cognitive impairments or addiction. PLMI alleviates oxaliplatin‐ and bortezomib‐induced neuropathic pain. The peptide PLMI adopts a turn conformation. Conclusion and Implications Our results suggest that GPER inverse agonists could be used to alleviate nociception and to protect against paclitaxel‐induced peripheral neuropathy. The turn conformation of the PLMI peptide in solution is in favour of a bioactive GPCR‐interacting peptide.
Genuine selective caspase-2 inhibition with new irreversible small peptidomimetics Elodie Bosc, Julie Anastasie, Feryel Soualmia, Pascale Coric, Ju Youn Kim, et al. Cell Death and Disease, 2022 Caspase-2 (Casp2) is a promising therapeutic target in several human diseases, including nonalcoholic steatohepatitis (NASH) and Alzheimer’s disease (AD). However, the design of an active-site-directed inhibitor selective to individual caspase family members is challenging because caspases have extremely similar active sites. Here we present new peptidomimetics derived from the VDVAD pentapeptide structure, harboring non-natural modifications at the P2 position and an irreversible warhead. Enzyme kinetics show that these new compounds, such as LJ2 or its specific isomers LJ2a, and LJ3a, strongly and irreversibly inhibit Casp2 with genuine selectivity. In agreement with the established role of Casp2 in cellular stress responses, LJ2 inhibits cell death induced by microtubule destabilization or hydroxamic acid-based deacetylase inhibition. The most potent peptidomimetic, LJ2a, inhibits human Casp2 with a remarkably high inactivation rate (k3/Ki ~5,500,000 M−1 s−1), and the most selective inhibitor, LJ3a, has close to a 1000 times higher inactivation rate on Casp2 as compared to Casp3. Structural analysis of LJ3a shows that the spatial configuration of Cα at the P2 position determines inhibitor efficacy. In transfected human cell lines overexpressing site-1 protease (S1P), sterol regulatory element-binding protein 2 (SREBP2) and Casp2, LJ2a and LJ3a fully inhibit Casp2-mediated S1P cleavage and thus SREBP2 activation, suggesting a potential to prevent NASH development. Furthermore, in primary hippocampal neurons treated with β-amyloid oligomers, submicromolar concentrations of LJ2a and of LJ3a prevent synapse loss, indicating a potential for further investigations in AD treatment.
Mixed Polymeric Micelles for Rapamycin Skin Delivery Guillaume Le Guyader, Bernard Do, Ivo B. Rietveld, Pascale Coric, Serge Bouaziz, et al. Pharmaceutics, 2022 Facial angiofibromas (FA) are one of the most obvious cutaneous manifestations of tuberous sclerosis complex. Topical rapamycin for angiofibromas has been reported as a promising treatment. Several types of vehicles have been used hitherto, but polymeric micelles and especially those made of d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) seem to have shown better skin bioavailability of rapamycin than the so far commonly used ointments. To better understand the influence of polymeric micelles on the behavior of rapamycin, we explored it through mixed polymeric micelles combining TPGS and poloxamer, evaluating stability and skin bioavailability to define an optimized formulation to effectively treat FA. Our studies have shown that TPGS improves the physicochemical behavior of rapamycin, i.e., its solubility and stability, due to a strong inclusion in micelles, while poloxamer P123 has a more significant influence on skin bioavailability. Accordingly, we formulated mixed-micelle hydrogels containing 0.1% rapamycin, and the optimized formulation was found to be stable for up to 3 months at 2–8 °C. In addition, compared to hydroalcoholic gel formulations, the studied system allows for better biodistribution on human skin.
Acetonitrile allows indirect replacement of nondeuterated lipid detergents by deuterated lipid detergents for the nuclear magnetic resonance study of detergent-soluble proteins Xiao Wang, Xiaowei Chen, Sylvie Nonin‐Lecomte, Serge Bouaziz Protein Science, 2021 Detergent‐soluble proteins (DSPs) are commonly dissolved in lipid buffers for NMR experiments, but the huge lipid proton signal prevents recording of high‐quality spectra. The use of costly deuterated lipids is thus required to replace nondeuterated ones. With conventional methods, detergents like dodecylphosphocholine (DPC) cannot be fully exchanged due to their high binding affinity to hydrophobic proteins. We propose an original and simple protocol which combines the use of acetonitrile, dialysis and lyophilization to disrupt the binding of lipids to the protein and allow their indirect replacement by their deuterated equivalents, while maintaining the native structure of the protein. Moreover, by this protocol, the detergent‐to‐protein molar ratio can be controlled as it challenges the protein structure. This protocol was applied to solubilize the Vpx protein that was followed upon addition of DPC‐d38 by 1H‐15N SOFAST‐HMQC spectra and the best detergent‐to‐DSPs molar ratio was obtained for structural studies.
The three lives of Pierre Boulanger Nathalie Chazal, Hugues de Rocquigny, Philippe Roussel, Serge Bouaziz, Françoise Barré-Sinoussi, et al. Retrovirology, 2020
Putative functional domains of human cytomegalovirus pUL56 involved in dimerization and benzimidazole D-ribonucleoside activity Antiviral Therapy, 2008
The 3-O-(3′,3′-dimethylsuccinyl) derivative of betulinic acid (DSB) inhibits the assembly of virus-like particles in HIV-1 Gag precursor-expressing cells Antiviral Therapy, 2007
