Catégorie d'actualités: significant publications

The first molecules which really prefer manganese(II) over zinc(II)

Manganese(II) complexes meet increasing interest in biomedical applications, in particular as potential Magnetic Resonance Imaging contrast agents with a better biocompatibility and safety profile than the currently used gadolinium(III) chelates. However, we severely lack chelating ligands that enable high MnII complex stability and especially good selectivity for manganese(II) versus zinc(II), the most relevant biological competitor. In an article published in Angewandte Chemie Int. Ed., the “Metal complexes and MRI” group in collaboration with the group of Peter Comba at the University of Heidelberg, has identified novel cage molecules which, for the first time, satisfy these criteria. The bispidine derivative ligands provide rigid and large coordination cavities that perfectly match the slightly larger size of MnII, yielding eight-coordinate MnII complexes with record stabilities. In contrast, the smaller ZnII ion cannot accommodate all ligand donors, resulting in highly strained and less stable six-coordinate complexes.

Combined theoretical and experimental data demonstrate unprecedented selectivity, with up to 10 orders of magnitude higher stability for the manganese(II) than for the zinc(II) analogues, in sharp contrast to usual coordination chemistry rules.

 

https://onlinelibrary.wiley.com/doi/full/10.1002/anie.202115580

A new luminescence for the direct follow-up of drug delivery

Liposomes are nanocapsules widely used for the in vivo transport and delivery of therapeutic or diagnostic agents, or both. The therapeutic agent will only become active upon its release, thus sparing healthy tissues. The follow up of such release process is crucial to understand and control the drug action.

The previously reported approaches are based on optical imaging, using exclusively organic fluorophores or inorganic nanoparticles, co-encapsulated with the drug in the liposome.

The use of luminescent lanthanide complexes is an alternative which offers a number of advantages, including the capacity of those complexes to emit in the near infrared (NIR) region, enabling their detection in biological media.

The CBM research teams have developed an original nanocapsule : a liposome comprising an Ytterbium complex encapsulated with doxorubicin (anticancer agent). The NIR emission of the lanthanide complex is only observed when the drug is encapsulated. This NIR luminescence signal can therefore enable the direct follow-up, and in real time, of the integrity of the liposome, and can thus be used to detect the drug release.

An in vivo proof of concept was performed and the lanthanide luminescent signal could be detected in a mouse model of breast cancer.

Références de l'article :

Doxorubicin-sensitized Luminescence of NIR-emitting Ytterbium Liposomes: Towards Direct Monitoring of Drug Release,

Sara Lacerda, Anthony Delalande, Svetlana V. Eliseeva, Agnès Pallier, Célia S. Bonnet, Frédéric Szeremeta, Sandra Même, Chantal Pichon, Stéphane Petoud, Eva Toth

Angewandte Chemie Int. Ed. 13 août 2021  https://doi.org/10.1002/anie.202109408

 

See the news on CNRS Chemistry Institute site

 

 




New methodological breakthrough in total protein synthesis

Since the first synthesis of an amino acid dimer in the late 19th century, synthetic proteins represented a fascinating goal for generations of chemists. Invented in the 1960s, the solid phase peptide synthesis (SPPS) technology is since used routinely for peptides made up of a few dozen amino acids. The discovery of "chemical ligation" reactions in the 1990s paved the way to the synthesis of proteins of more than one hundred amino acids: extremely selective chemical reactions are used under aqueous conditions to couple peptide segments - themselves synthesized by SPPS -, devoted of side chain protective groups usually required in organic synthesis. Thanks to these methodological breackthroughs, the chemical approach to protein synthesis today advantageously complements biotechnological methods and enable the generation of native or modified proteins, tailor-made tools for deciphering biological processes at atomic resolution.

However, the synthesis of proteins of several hundred amino acids requires numerous successive chemical ligations, and therefore particularly delicate stages of purification of the reaction intermediates. One solution to overcome these steps is to assemble the proteins onto a solid support. Although very attractive, this approach has been limited to proofs of concept: one of the main reasons is the difficulty of grafting on a suitable solid support the first peptide segment through a linker that can be easily cleaved once the ligations carried out. Indeed, the conditions required for cleaving the linkers developed so far are incompatible with many proteins.

To overcome this problem, CBM scientists, in collaboration with colleagues from IC2MP in Poitiers, explored linkers programmed to be cleaved under very mild conditions by an enzymatic reaction. Remarkably, the size of the enzyme directly correlates with the rate at which the arm is cleaved, and therefore with the efficiency of the release of the synthesized protein. The method was applied to the synthesis of a peptide of 160 amino acids, which is to date the longest sequence ever synthesized by solid phase chemical ligations.

Reference of the article : S. A. Abboud, M. Amoura, J.-B. Madinier, B. Renoux, S. Papot, V. Piller, V. Aucagne. Enzyme-cleavable linkers for protein chemical synthesis through solid-phase ligations, Angew. Chem. Int. Ed., 2021, accepted article. https://doi.org/10.1002/anie.202103768

See the news on the website of the CNRS institute of chemistry




J.-M. Bonmatin co-author of a letter in Science (July 16, 2021)

A group of co-authors, specialists in pollinators, has just published a letter in Science (Simon-Delso at al. 2021). The letter is a call to European Ministers to act responsibly and reduce toxic risks to pollinators in pesticide assessments. For example, while the natural mortality of honeybees can reach up to 5%, the scientific community agrees on a maximum "acceptable" rate of 7% for a pesticide. To accept 10% is to take a risk that is far too high in view of the already catastrophic situation regarding the collapse of pollinators. Because of the crucial importance of such decisions for the planet and our future, the authors and publisher have chosen a more direct style than usual to get their message across.

Reference : Simon-Delso N, Aebi A, Arnold G, Bonmatin JM, Hatjina F, Medrzycki P & Sgolastra F (2021) Maximize EU pollinator protection: Minimize risk, Science, 373(5552), 290. DOI: 10.1126/science.abj8116




How the hydrothermal environment of Primeval Earth may have influenced the choice of sugar in DNA and RNA

CBM scientists give answers in a publication published in the Journal Nature Communications. Why is Furanose the only sugar found in the composition of DNA and RNA while this form of sugar is not the most stable, so not the most abundant, in temperature conditions and pressure we are currently experiencing? These are the hydrothermal sources, omnipresent on the surface of the primitive land, and their complex thermal influence, which could be at the origin of this selectivity. This study conducted by scientists from the Molecular Biophysics Center, which is the subject of an article in the Nature Communications journal, should make it possible to better understand why and how molecules come together to give life in a primitive geological context.

Reference

Avinash Vicholous Dass, Thomas Georgelin, Frances Westall, Frédéric Foucher, Paolo De Los Rios, Daniel Maria Busiello, Shiling Liand & Francesco Piazza
Equilibrium and non-equilibrium furanose selection in the ribose isomerisation network
Nature Communications, 12 2749 (2021) https://www.nature.com/articles/s41467-021-22818-5

See the news on the site of the Institute of Chemistry

 




When a non-conserved protein domain becomes essential

Rho-dependent termination of transcription is a critical regulatory mechanism specific to bacteria. In a subset of species including most Actinobacteria and Bacteroidetes, the Rho factor contains a large, poorly conserved N-terminal insertion domain (NID) of cryptic function. Through the first characterization of an actinobacterial Rho factor containing a very large NID (~40% of total mass), we show that such a non-conserved protein domain can be essential for activity. Without NID, the Rho factor of Bacteroides fragilis (BfRho) indeed cannot induce transcription termination and displays a reduced affinity for RNA. Intriguingly, the presence of a NID in BfRho is not correlated to the lack of residues or motifs deemed essential in NID-less Rho factors from evolutionary distinct species. The NID requirement is probably linked to the coevolution of partner feature(s) such as lineage-specific RNA polymerase domains and/or low G+C content of the B. fragilis transcriptome. Our data thus highlight that ‘essential function’ does not always rhyme with ‘structural conservation’.

Simon I., Delaleau M., Schwartz A., Boudvillain M.
A Large Insertion Domain in the Rho Factor From a Low G + C, Gram-negative Bacterium is Critical for RNA Binding and Transcription Termination Activity
Journal of Molecular Biology (2021) 433 (15) 167060 - Doi : 10.1016/j.jmb.2021.167060




Biodiversity skepticism?

Biodiversity skepticism?

Based on analysis of time series of abundances of insect species in the United States, Crossley et al. reported in Nature Ecology & Evolution (August 2020) that there is no evidence of a global decline in insect abundance or diversity in the United States, this for both natural and anthropogenic sites. Their study described the apparent robustness of insect populations in the U.S. as reassuring, in contrast to recent studies reporting dramatic declines in their abundance around the world.

However, a multidisciplinary consortium including researchers from INRAE, the University of Rennes and CNRS identified major problems in the Crossley et al. paper concerning: 1) statistical analysis and 2) inconsistencies in data selection. The consortium demonstrates, in a commentary published in Nature Ecology & Evolution Desquilbet et al. , that these biases call into question the conclusions of Crossley et al.

This is the second time (see here) that a high-ranking publication downplaying insect declines has been subject to methodological criticisms. These studies raise the question of a "biodiversity-skepticism" within the scientific community. In order to implement an appropriate protection of biodiversity, public decision-makers need an informed diagnosis that is not clouded by biased studies which slow down decision-making.

Reference :
Desquilbet M, Cornillon PA, Gaume L & Bonmatin JM (2021)
Matters arising: Adequate statistical modelling and data selection are essential when analysing abundance and diversity trends
Nature Ecology & Evolution doi : https://www.nature.com/articles/s41559-021-01427-x