NMR of Biomolecules: Antimicrobials, Toxins and Metabolites
The team's research contributes to the development of new compounds with antimicrobial or insecticide activity, the identification of new therapeutic targets, or participates in the development of new photoactivatable drugs. Our activities are mainly based on the use of NMR in structural biology and metabolomics. Disulfide Rich Peptides (DRP), AntiMicrobial Peptides (I) and toxins (II) are our privileged subjects of study, and determining their 3D structure is one of the steps in understanding their mechanisms of action. In the CoViD context of recent years, we are also interested in the analysis of spike protein structures for vaccine development (IV). Metabolomics (III), is essentially developed on Drosophila models of human pathologies, to understand which metabolic pathways are impacted by diseases.
I. ANTIMICROBIAL PEPTIDES (Rich in Disulfide Bridges)
Antimicrobial peptides (AMPs), key molecules in the innate immunity of all living organisms, represent one of the most promising alternatives to fight antibiotic resistance, a major public health problem. We are working on a fine understanding of the 3D structures (structural diversity, structure-activity relationships, evolution of structures via phylogeny) and the fine understanding of the mechanisms of action of some promising original AMPs, to help designing new antimicrobial compounds. Avian-double-beta-defensins.
Avian-double-beta-defensins
Ancestral oyster defensins
King penguin defensins
Other disulfide-rich peptides (Toxines)
Toxins rich in disulfide bridge have strong structural identities with the antimicrobial peptides described above. We study toxins of various origins (plants, ants, spiders, scorpions). We work on the fine understanding of structures (structural diversity, structure-activity relationships, evolution of structures during the evolution of species) to improve understanding of mechanisms of action and participate in the design of the new insecticide compounds. Finally, we are involved in several projects on photo-activatable toxins, which open new therapeutic avenues.
Plant insecticidal toxins
Insecticidal toxins from ant venoms
Photo-activatable scorpion or spider toxins
III. METABOLOMICS
We are developing NMR-based metabolomics analysis, mainly on Drosophila models of human pathologies such as gliomas (Maravat et al. 2021, Bertrand et al. 2023), Huntington's disease (Bertrand et al. 2020) and Parkinson's disease. Other analyses are also being carried out to study different effects, such as that of a therapeutic treatment. The aim of these studies is to identify the metabolic pathways impacted by the diseases in order to better understand them at the molecular level and enable the identification of new therapeutic targets.
Fig7: Graphical summary of a metabolomics study on the example of Huntington's disease (Bertrand et al. 2020): i) Construction of the Drosophila model carrying Huntington's disease, ii) NMR analyses, iii) Statistical analyses and iv) Identification of disease biomarkers.
Fig8:13C-HSQC NMR spectra of extracts from control (blue) and glioma (red) Drosophila, fed 13C glucose. .Signals from lipids (clearly visible on enlargements) are considerably reduced in flies carrying gliomas, while lactate is increased (Bertrand et al. 2023).
STRUCTURAL BIOLOGY FOR THE DEVELOPMENT OF SARS-COV-2 VACCINES
Through our expertise in structural biology of proteins, we participated, in collaboration with the Finlay Vaccine Institute of Cuba, in the development of SOBERANA vaccines against COVID19, based on the recombinant protein RBD, SARS-CoV-2 spike protein binding domain on ACE2 receptor.
Fig9: The recombinant RBD protein is used in SOBERANA vaccines (Valdes et al ACS Central Sciences 2021) either as a dimer (Santana et al 2022) or conjugated with tetanus anatoxin (Valdes et al ACS ChemBio 2021).