Reference : ABG-38625
Offer type : job
Contract : Contract/Project
Salary range : To negociate
Employer : Commissariat à l’Energie Atomique et aux Energies Alternatives - Groupe
Workplace : GRENOBLE - FRANCE
Skill area : Chemistry - Organic, mineral, industrial chemistry + - Biology, Medicine, Health
Posting date : 1/3/2012
Application deadline : 2/1/2012

The project will be developed in the “Laboratoire de Chimie Inorganique et Biologique”, which is a joined unit between CEA and Grenoble University (UMR_E 3) in the Institute of Nanosciences and Cryogeny. This laboratory is carrying high-level fundamental research in the field of inorganic and/or biological chemistry.

Mission :

The position is a 2-years post-doctoral fellowship, funded by a grant of FRM (Fondation pour la Recherche Médicale” on a project entitled “Rational design of intracellular copper chelators for treating hepatic copper overload in Wilson’s disease”.
The beginning of the contract should be before June 15th of 2012.

Context :

The Wilson’s disease is a rare disease due to the dysfunction of a protein responsible for the excretion of excess copper from the body, the Wilson’s ATPase or ATP7B. It results in a hepatic copper overload that is lethal if not diagnosed. The current treatments are poorly selective for copper and induce major side effects. Therefore, we propose an original chemical approach for the development of innovative therapeutic molecules to fight copper overload in the liver of Wilson’s disease patients.[1] It is a societal issue to design more efficient chelators that are (i) highly selective for copper to avoid disturbance of other essential metals like zinc and (ii) targeted at the liver, where copper is accumulated, to avoid copper chelation at other places in the body. We have already designed very efficient Cu(I) chelating molecules [2] and our collaboration between chemists and biologists has already led to the design of two hepatocyte-targeted chelators that are highly selective for copper and chelate this metal in hepatic cells.[3]

Project :

This project aims at optimizing the chemical structures of the first two molecules. To do so, the mechanisms of intracellular copper chelation and detoxification will be analyzed in hepatic cells by evaluating the role of essential features such as the affinity of the molecule for copper, the type of complexes formed with copper, or the position of the targeting system in the molecule. Such fundamental information about intracellular copper chelation will afford crucial clues for the design of efficient drug candidates for the Wilson’s disease.
The post-doctoral fellow will therefore be involved in organic synthesis optimization and purifications. He (or she) will also characterize metal-chelator interactions in vitro and will participate in the cellular assays to evaluate the in vivo efficiency of the synthesized molecules.

• [1] P. Delangle, E. Mintz, Dalton Trans., 2012, in press
• [2] A. M. Pujol, C. Gateau, C. Lebrun and P. Delangle, J Am Chem Soc, 2009, 131, 6928 A. M. Pujol, C. Gateau, C. Lebrun and P. Delangle, Chem. Eur. J., 2011, 17, 4418.
• [3] A. M. Pujol, M. Cuillel, O. Renaudet, C. Lebrun, P. Charbonnier, D. Cassio, C. Gateau, P. Dumy, E. Mintz and P. Delangle, J. Am. Chem. Soc., 2011, 133, 286.

Candidates profile :

The candidate should have a PhD in chemistry either in inorganic or biological chemistry, with several publications on the subject.
Very good skills in organic synthesis and HPLC purification are required.
Skills in cellular experiments would be greatly appreciated as he (or she) will collaborate with biologists for the cellular assays.

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