Catégorie d'actualités: significant publications

Luminous crowns to see into the heart of life

The members of the ‘Luminescent Lanthanide Compounds, Optical Spectroscopy and Bioimaging’ team have been working for many years on the design and synthesis of supramolecular complexes based on lanthanides emitting in the near infrared, which function as optical imaging agents for biological experimentation and medical diagnosis. They have designed lanthanide-containing metallacrown complexes that have proven to be very promising candidates due to their very high brightness. However, until now, these metallacrowns had a significant limitation due to their excitation wavelengths, which were limited to the ultraviolet part of the electromagnetic spectrum. These wavelengths pose a problem for biological imaging because they can severely disrupt or damage the biological system being observed.

They have overcome this major limitation by designing and synthesising a new family of metallacrowns that have lanthanide sensitizers that can be excited in the visible range of the electromagnetic spectrum. The structure of these metallacrowns is innovative: the sensitizers are attached to the periphery. Thanks to this approach, researchers were able, for the first time, to use a metallacrown to label living cells and image them using near-infrared microscopy. This work opens up major prospects for the use of lanthanide-based molecular complexes for near-infrared imaging in vitro and in vivo.

This major innovation was reported by CNRS Chemistry on its website.

Caption: Near-infrared luminescence image superimposed on the white light image obtained from living HeLa cells in which lanthanide metallacrowns, whose structure appears inlaid, were incubated.

Article references:
Novel lanthanide( III)/gallium( III) metallacrowns with appended visible-absorbing organic sensitizers for
molecular near-infrared imaging of living cells
Timothée Lathion, Julie Bourseguin, Svetlana V. Eliseeva, Matthias Zeller, Stéphane Petoud, Vincent L. Pecoraro
Chemical Science, 2025, 16, 12623. https://doi-org.insb.bib.cnrs.fr/10.1039/D5SC01320H

Evaluation of synthetic mRNA with selected UTR sequences and alternative Poly(A) tail, in vitro and in vivo

Messenger RNA (mRNA) has emerged as an attractive new technology of drugs. The efficacy of mRNA technology depends on both the efficiency of mRNA delivery and translation. Untranslated regions (UTRs) and the poly(A) tail play a crucial role in regulating mRNA intracellular kinetics. Intending to improve the therapeutic potential of synthetic mRNA, CBM researchers evaluated various UTRs and tail designs, using Pfizer-BioNTech COVID-19 vaccine sequences as a reference. First, they screened six 5’ UTRs (capdependent/independent), evaluated nine 5’ UTR-3’ UTR combinations, and a novel heterologous A/G tail in cell models, and in vivo using luciferase as a reporter gene.

Then, to decipher the translation mechanism of selected UTRs, they correlated mRNA expression with ribosome load, mRNA half-life, mRNA immunogenicity, and UTR structures. Results showed that the heterologous tail they introduced is as potent as the Pfizer-BioNTech tail and confirmed the high potency of the human α-globin 5’ UTR.

They also revealed the potential of the VP6 and SOD 3’ UTRs. Researchers validated their results using mRNA encoding the SARS-CoV-2 spike protein formulated as lipid nanoparticles (LNPs) for mouse immunization. Overall, the selected 3’ UTRs and heterologous A/G tail have great potential as new elements for therapeutic mRNA design.

These results open up new prospects for mRNA therapies. While improvements are still needed to achieve higher expression than existing strategies, this strategy contributes to improving mRNA therapies.

These results are linked to a patent

Reference:
Evaluation of synthetic mRNA with selected UTR sequences and alternative Poly(A)  tail, in vitro and in vivo. Medjmedj A, Genon H, Hezili D, Ngalle Loth A, Clemençon R , Guimpied C, Mollet L, Bigot A, Wien F, Hamacek J, Chapat C, Perche F, Molecular Therapy Nucleic Acids 2025.

A CBM team has developed a contrast agent capable of revealing oxidative stress in living tissue

The "Metal Complexes and MRI" team, in collaboration with a Hungarian team, has developed a contrast agent based on an iron compound associated with a fluorinated ligand. This makes it possible to map oxidative stress in living tissue, a marker of numerous pathologies. This molecular detector, still at the pre-clinical stage, could considerably enrich tomorrow's medical imaging toolkit.

This major advance has been published in the journal JACS.
Relaxation-Based In Vivo Discrimination of Oxidized and Reduced States of a Redox-Switchable 19F MRI Probe
Garda Z., Szeremeta F., Tóth C.S., Bunda S., Pifferi C., Clémençon R., Même S., Tircso G., Tóth É.
J. Am. Chem. Soc. 2025, 147, 21, 18017-18024

Find out more on the CNRS Chimie website.

 

Combination of nanomedicine and biophysics methods to characterize mRNA liposomes

This new optimised version of liposomes has been reported by CNRS Chimie on its website.

The development of lipid-based mRNA delivery systems has significantly advanced mRNA-based therapies. Liposomes, in particular histidylated liposomes (LYX), have been shown to be effective in delivering nucleic acids. In this study, LYX liposomes were optimised by adding a freeze-drying and extrusion step, resulting in improved homogeneity and storage stability. LYX liposomes maintained their size (150 ± 10 nm) and polydispersity index (0.10 ± 0.02) for up to a year at 4°C, while preserving their transfection efficiency. They exhibit a high mRNA encapsulation rate (∼95%) and protect it from degradation by RNases. The lamellar organisation was confirmed by small-angle X-ray scattering and CryoTEM. These liposomes allow efficient transfection of cell lines and primary cells, albeit with lower efficiency than commercial vectors, due to slower cell internalisation and reduced endosomal escape. They have demonstrated their ability to deliver mRNA encoding the therapeutic molecules BMP2 and BMP9, leading to the production of functional proteins capable of inducing BMP signalling. In vivo studies have also confirmed their potential for mRNA delivery when incorporated into hydrogels and implanted subcutaneously in mice. These results show that LYX liposomes are a promising and versatile platform for mRNA delivery in therapeutic applications.

This work involved laboratories from two institutes: the Centre de Biophysique Moléculaire (CNRS Chimie) and the Laboratoire de Biologie, Bioingénierie et Bioimagerie Ostéo-Articulaires (CNRS Ingénierie).

Reference:
Albert Ngalle Loth, Manon Maroquenne, Ayoub Medjmedj, Franck Coste, Thomas Bizien, Chantal Pichon, Delphine Logeart-Avramoglou, Federico Perche.
Structural and functional characterization of a histidylated liposome for mRNA deliveryStructural and functional characterization of a histidylated liposome for mRNA delivery.
Journal of Controlled Release (2025) Volume 379, pages 164-176, doi: 10.1016/j.jconrel.2025.01.010.

A butterfly peptide to combat resistant fungi

A promising avenue for better crop protection and perhaps even for treating certain diseases, as reported by CNRS Chimie.

Fungal infections represent a major global health problem, with increasing resistance to currently available antifungal molecules. Targeting glucosylceramides (GlcCer), which are functionally essential glycosphingolipids present in fungal membranes, represents a promising strategy for the development of new antifungal agents.

GlcCer are associated with the antifungal activity of certain antimicrobial peptides found in plants and insects, known as defensins. The ETD151 peptide, optimised from butterfly defensins, is active against a range of fungal pathogens of interest to human health and agriculture. For example, the researchers have previously shown that ETD151 induces a multifaceted mechanism of action on Botrytis cinerea, a multi-resistant phytopathogenic fungus used here as a model (Aumer et al. 2020).

This multifaceted mechanism of action makes ETD151 a promising candidate for combating fungal resistance. The researchers took up the challenge of identifying its molecular target. They showed that the ETD151 peptide binds at the molecular level to GlcCer and localises preferentially to the membrane, where it induces various toxic effects. Identifying its molecular target and understanding the mode of action of ETD151 opens up new prospects for human health and crop protection.

Reference :
O. Kharrat, Y. Yamaryo-Botté, R. Nasreddine, S. Voisin, T. Aumer, B.P.A. Cammue, J. Madinier, T. Knobloch, K. Thevissen, R. Nehmé, V. Aucagne, C. Botté, P. Bulet, & C. Landon.
The antimicrobial activity of ETD151 defensin is dictated by the presence of glycosphingolipids in the targeted organisms.
Proc. Natl. Acad. Sci. U.S.A. (2025) 122 (7) e2415524122, https://doi.org/10.1073/pnas.2415524122.

Improved protocol for metabolite extraction and identification of respiratory quinones in extremophilic Archaea grown on mineral materials.

We investigated the metabolome of the iron- and sulfur-oxidizing, extremely thermoacidophilic archaeon Metallosphaera sedula grown on mineral pyrite (FeS2). The extraction of organic materials from these microorganisms is a major challenge because of the tight contact and interaction between cells and mineral materials. Therefore, we applied an improved protocol to break the microbial cells and separate their organic constituents from the mineral surface, to extract lipophilic compounds through liquid–liquid extraction, and performed metabolomics analyses using MALDI-TOF MS and UHPLC-UHR-Q/TOF. Using this approach, we identified several molecules involved in central carbon metabolism and in the modified Entner-Doudoroff pathway found in Archaea, sulfur metabolism-related compounds, and molecules involved in the adaptation of M. sedula to extreme environments, such as metal tolerance and acid resistance. Furthermore, we identified molecules involved in microbial interactions, i.e., cell surface interactions through biofilm formation and cell–cell interactions through quorum sensing, which relies on messenger molecules for microbial communication. Moreover, we successfully extracted and identified different saturated thiophene-bearing quinones using software for advanced compound identification (MetaboScape). These quinones are respiratory chain electron carriers in M. sedula, with biomarker potential for life detection in extreme environmental conditions.

Reference :
Gfellner SV, Colas C, Gabant G, Groninga J, Cadene M, Milojevic T. Improved protocol for metabolite extraction and identification of respiratory quinones in extremophilic Archaea grown on mineral materials. Front Microbiol. 2025 Jan 8;15:1473270. doi: 10.3389/fmicb.2024.1473270

Will it be possible to soon detect copper by non invasive imaging?

In this work, in collaboration with chemists from the Institut de Chimie de Strasbourg (CNRS/Université de Strasbourg), we have designed and studied a smart MRI probe; which is switched on in the presence of copper. The design of such probes is a real challenge as free Cu(II) in vivo is present in very low quantities, typically lower than Zn(II), another physiological cation. It is therefore of prime importance to conceive probes with a maximal turn on response in the presence of Cu(II), and an excellent selectivity towards Zn(II). The probes are typically composed of an MRI active site, a linker and a Cu(II) binding site. The use of small complexing units for Cu(II) binding makes it very difficult to obtain a good selectivity. Here, we have used a bioinspired approach where the Cu(II) binding site is based on the ATCUN motif, a small peptide that binds Cu(II) in the blood. Thanks to this design, the probe displays an unprecedented turn on response, and importantly an excellent selectivity for Cu(II) vs Zn(II). Phantom MRI images obtained closed to physiological conditions show a bright contrast, illustrating the potential of such probes.

Reference :
A Bioinspired Cu2+-Responsive Magnetic Resonance Imaging Contrast Agent with Unprecedented Turn-On Response and Selectivity
Katharina Zimmeter, Agnès Pallier, Bertrand Vileno, Martina Sanadar, Frédéric Szeremeta, Carlos Platas-Iglesias, Peter Faller, Célia S. Bonnet and Angélique Sour
Inorganic Chemistry - Vol 63 - Issue 49 - 23067−23076