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Laboratory | Pharmacology


LTMB

Toxins, receptors and ion channels

Published on 27 November 2017
Our research aims first to identify new toxins with original biological properties, secondly to characterize pharmacologically and structurally their interaction on their molecular targets, thirdly to change their functional properties by directed engineering and finally to exploit these ligands as tools to study these receptors and channels or as therapeutic agents. Furthermore, our work also aim to develop new detection systems of neurotoxic agents, based on their interaction with their molecular targets involved in nerve conduction and skeletal muscle contraction.

Team Leader
Denis SERVENT
denis.servent@cea.fr

Research pursued in our team aim to exploit the vast resource of toxins present in venoms and that have been selected during the evolution process to target very efficiently and selectively molecular targets that play a major physiological role. To this end, we particularly studied the interaction of different peptide toxins with many receptors and ion channels, particularly those interacting with G-protein coupled receptors (GPCRs) and sodium channels.

Our objectives are :

  • to identify new toxins with original pharmacological property and targeting GPCR or ion channels of interest
  • to determine at the molecular level the functional determinants involved in these interactions
  • to propose experimentally-based structural models of these toxins-receptor complexes
  • to use this knowledge to better understand the origin of the selectivity and function of these ligands
  • to design engineered molecules with news functional properties.

Our works have led for example to the characterization of new toxins interacting with nicotonic acetylcholine, alpha-adrenergic, muscarinic, somatostatin, dopamine and vasopressin receptors as well as with various sodium channel subtypes. Part of these new toxins have been patented due to their unique pharmacological properties, some of which are still being studied in animal models of human diseases. Pharmacological characterization and structural modeling of some of these complexes (MT7 toxin -muscarinic M1 receptor, rho-toxin Da1A -alpha1A adrenoceptor) allowed us to better understand the molecular basis of their functional properties and allow the engineering of these structural platforms such as the three-finger fold toxins.

 

On the other hand, our involvement in the European programs Conco (2007-2011) and Venomics (2011-2015) led us to significantly improve our ability to synthesize these toxins, our ability to perform pharmacological and functional characterization of their interactions and in a more general way allows us to better understand the huge diversity of toxins present in venoms.
 
Our team is also involved in a research program aiming to understand the mode of action of shellfish toxins produced by micro-organisms (dinoflagellates) and known to  cause severe neurotoxic effect via their accumulation in bivalves (mussels, oysters ...). These molecules (gymnodimines, spirolides, pinnatoxines) contain a cyclic imine chemical group and we have shown recently that they interact very efficiently with central and peripheral nicotinic acetylcholine receptors.

These studies are supported by the ANR program ASTRID (AquaNeuroTox), whose aim is first the identification and characterization of the mode of interaction of neurotoxic shellfish toxins and secondly the development of detection systems adapted to these molecules on the basis of their interaction with their receptors / ion channels target.


Publications

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