Typologie d'actualités: Group NMR of Biomolecules

Mimicking the butterfly’s natural defenses to develop future antifungal compounds.

Fungal infections are a threat to human health and agriculture. It is therefore essential to develop new antifungal compounds with innovative mechanisms of action. Fungal glucosylceramides (GlcCer), which are essential for fungal pathogenicity, are a promising target.

The ETD151 peptide, optimized from butterfly defensins, acts against human fungal pathogens on the WHO priority list and plant pathogens such as B. cinerea used as a model. We recently showed that fungal GlcCers are the molecular target of the ETD151 peptide in the very first step of the mechanism of action (Kharrat et al PNAS 2025).

Through this study, which combines biophysical and spectroscopic methods, we reveal the key structural elements of the interaction between the ETD151 peptide and GlcCer at the molecular level. In particular, the presence of a methyl group specific to fungal GlcCer plays a role in the membrane disorder induced by the peptide and increases the binding affinity between the partners.

These results pave the way for the optimization and development of defensin mimics to selectively combat pathogenic fungi by targeting methylated GlcCer while minimizing toxicity to the host.

References:
Molecular recognition of fungal methylated glucosylceramides by ETD151 defensin.
Ons Kharrat, Françoise Paquet, Rouba Nasreddine, Jean-Baptiste Madinier, Reine Nehmé, Vincent Aucagne, Philippe Bulet, Dror Warschawski, and Céline Landon.
Journal of Biological Chemistry Volume 301, Issue 9, 110587
doi: 10.1016/j.jbc.2025.110587

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.

Research on glioma (brain tumor) carried out at the CBM highlighted by CNRS Chimie

The use of different original NMR methods (MRI, 1H HR-MAS, 2D liquid NMR) made it possible to characterize a glioma model established in adult Drosophila and to reveal the therapeutic potential of a serotonin receptor for the treatment of these cancers.

Read the CNRS Chimie article.

Read the "Actualité chimique" article n° 492, 2024, February

Gliomas account for 50% of brain cancers and therefore constitute the most common brain tumors. Molecular alterations involved in adult gliomas have been identified and mainly affect tyrosine kinase receptors with amplification and/or mutation of the epidermal growth factor receptor (EGFR) and its associated signaling pathways. Several targeted therapies have been developed but current treatments remain ineffective for glioblastomas, the most severe forms. Thus, it is a priority to identify new pharmacological targets. Here, we used a Drosophila glioma model in adult, to characterize metabolic disturbances associated with glioma and assess the consequences of the serotonin 5-HT7 receptor expression on glioma development. First, by using in vivo Magnetic Resonance Imaging, we have shown that expression of the constitutively active forms of EGFR and PI3K in adult glial cells induced enlargement of brains. Then, we explored altered cellular metabolism by using High-Resolution Magic Angle Spinning NMR and 1H-13C Heteronuclear Single Quantum Coherence solution state. Discriminant metabolites identified highlight rewiring of metabolic pathways in glioma, and associated cachexia phenotypes. Finally, the expression of 5-HT7R in this model attenuates phenotypes associated with glioma development (brain enlargement and cachexia).

Article :
An adult Drosophila glioma model to highlight metabolic dysfunctions and evaluate the role of the serotonin 5-HT7 receptor as a potential therapeutic target.
Bertrand M, Szeremeta F, Hervouet‐Coste N, Sarou-Kanian V, Landon C, Morisset-Lopez S, Decoville M
The FASEB Journal. 2023 37:e23230. doi:10.1096/fj.202300783RR