CE34 - Contaminants, écosystèmes et santé

Bioprospecting, discovery, mode of action & biosynthesis of marine biotoxins – ICH-NEURO-MET

ICH-NEURO-MET : Bio prospection, découverte, mode d’action et biosynthèse de biotoxines marines

The chemical biology of phytoplankton is needed fot the interaction with their environment through symbiosis, parasitism, allelopathy, defense, attack, among others behaviors. The chemical diversity is explained by the emergence and on-going evolution of secondary metabolism biosynthetic pathways and could lead to novel cholinergic neurotoxins of interest for developing front-line drugs for neurodegenerative disorders and new ichthyotoxic (fish-toxic) compounds for conceiving antitumoral drugs

The aim of ICH-NEURO-MET is to discover novel neurotoxic and ichthyotoxic (fish-toxic) compounds with original scaffolds, establish their structure, their mode of action and their biosynthetic routes.

Phytoplankton lifestyle is characterized by episodic blooms attaining high cell densities and covering large sea surfaces. When dominated by toxin-producing species, harmful algal blooms constitute a potential threat for public health and aquaculture activities resulting in huge annual economic losses totaling hundreds of millions of dollars worldwide. Aside their negative impacts on animal wildlife, human health and socio-economical activities, the bright side of toxins is their mode of action, which enables a better understanding of their molecular targets and the conception of novel drugs. Marine organisms such as dinoflagellates, are interesting sources of never-ending original bioactive compounds, fueled by the emergence and on-going evolution of biosynthetic pathways in secondary metabolism and metabolic transformations in hosting organisms. As the world population grows older, neurodegenerative disorders will become a major daunting public health problem in the next decades. On the one hand, ICH-NEURO-MET seeks for ichthyotoxic compounds responsible for massive fish-killing in the oceans with cytotoxic and apoptotic properties for conceiving novel antitumoral molecules. On the other hand, ICH-NEURO-MET seeks for neurotoxic compounds for their use as blueprints to conceive new drugs targeting acetylcholinesterase and neuronal nicotinic acetylcholine receptors that are involved in a series of neurodegenerative disorders such as Alzheimer’s Disease, Parkinson, autism or addiction.

ICH-NEURO-MET aims to encompass the discovery and structural elucidation of dinoflagellate novel compounds with the unravelling of their mode of action and their biosynthetic pathways. To this end, we propose a novel approach consisting in building molecular networks from high resolution mass spectrometry (HRMS) data at the early stages of the bio-guided purification of compounds. This will accelerate the discovery of toxin congeners that are produced in very low amounts by the selected unicellular dinoflagellates. NMR spectra coupled to existing deep-learning algorithms, will also contribute to discover clustered bioactive metabolites. The methods used for bio-guided purification of hit compounds are: i) in-house developed ligand-binding assay for high-throughput monitoring of nicotinic acetylcholine receptor ligands, ii) in-house developed inhibition assay for acetylcholinesterase inhibitors screening, and iii) cytotoxic gill-based assays for ichtyotoxicity screening. The mode of action of the purified hit-compounds will be characterized by using electrophysiological, enzymological and toxicological techniques. Structure elucidation, at the heart of this project, will be performed by NMR and HRMS. To have an insight into the biosynthetic pathways of these novel secondary metabolites we will apply metabolic labeling using isotopic precursors. We will next use genomics and transcriptomics to annotate putative biosynthetic gene clusters

Does not apply

On a long perspective, the results obtained in this basic research program may have an impact on the treatment of neurodegenerative disorders and cancer, as well as on seafood safety. Together with well characterized novel molecules with interesting activities, we anticipate a great improvement in toxin diversity knowledge, dinoflagellate toxin biosynthesis and the understanding of the physiological role of toxins on dinoflagellate producers.

Does not apply.

ICH-NEURO-MET is an ambitious Franco-Austrian collaborative project to discover novel neurotoxic and ichthyotoxic compounds with original scaffolds, determine their structure and mode of action and shed light on their biosynthetic pathways. On a long perspective, the results obtained in this basic research program may have an impact on the treatment of neurodegenerative disorders and cancer, as well as on seafood safety.
Phytoplankton lifestyle is characterized by episodic blooms attaining high cell densities and covering large sea surfaces. When dominated by toxin-producing species, harmful algal blooms constitute a potential threat for public health and aquaculture activities resulting in huge annual economic losses totaling hundreds of millions of dollars worldwide. The bright side of toxins is their mode of action, which enables a better understanding of their molecular targets and the conception of new drugs. Marine organisms such as dinoflagellates, are interesting sources of never-ending original bioactive compounds, fueled by the emergence and on-going evolution of biosynthetic pathways in secondary metabolism and metabolic transformations in hosting organisms. As the world population grows older, neurodegenerative disorders will become a major daunting public health problem in the next decades. The discovery of natural cholinergic neurotoxins with novel scaffolds and the elucidation of their mode of action is very useful to develop front-line drugs for neurodegenerative disorders and addiction. Ichthyotoxins that are at the origin of massive fish-kill events worldwide may be of interest to conceive novel antitumoral drugs as well.
ICH-NEURO-MET is at the crossroads joining natural products chemistry, metabolomics, structural chemistry, toxicology and pharmacology specialized groups from France and Austria, to discover novel neurotoxic and ichthyotoxic compounds with original scaffolds. ICH-NEURO-MET aims to encompass the discovery and structural elucidation of dinoflagellate novel compounds with the unravelling of their mode of action and their biosynthetic pathways. We propose a novel approach consisting in building molecular networks from high resolution mass spectrometry (HRMS) data at the early stages of the bio-guided purification of compounds. This will accelerate the discovery of toxin congeners that are produced in very low amounts by the selected unicellular dinoflagellates. The mode of action of such compounds will be characterized by using electrophysiological, enzymological and toxicological techniques. NMR spectra coupled to existing deep-learning algorithms, will also contribute to discover clustered bioactive metabolites. Structure elucidation, at the heart of this project, will be performed by NMR and HRMS. Furthermore, to propose biosynthetic pathways for these novel secondary metabolites we will apply metabolic labeling techniques using 13C and 15N labeled precursors. We will next use transcriptomics under different culture/stress conditions and putative biosynthetic gene clusters will be annotated by using on-line tools that enable the prediction of biosynthetic enzymes function from transcriptomics data. Furthermore, functional transcriptomics will yield a better understanding on how adverse environmental factors, stressors or predators trigger or inhibit toxin biosynthesis, which is important to understand the physiological role of such toxins in the dinoflagellate producers.
Together with well characterized (structure, mode of action) novel molecules with interesting activities, we anticipate a great improvement in dinoflagellate toxin biosynthesis and toxin diversity knowledge. The complementarity and expertise of the Partners are well-suited to reach these challenging objectives.

Project coordinator

Monsieur Romulo ARAOZ (Service d'Ingénierie Moléculaire des Protéines)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

SIMOPRO Service d'Ingénierie Moléculaire des Protéines
BioNMR Plate-Forme Technologique de RMN Biologique
LMC-UNIVIE Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna

Help of the ANR 350,667 euros
Beginning and duration of the scientific project: February 2022 - 42 Months

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