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Synthesising Modified DNA for Therapeutic Ends

A Model Project of the European Associated Laboratory for Biomolecular Engineering

Working in partnership with three laboratories from the Free University of Brussels, the "Molecular engineering and bio-organic chemistry" group of the Laboratory for Dynamic and Structural Studies of Selectivity (LEDSS)1 has created a European laboratory without walls*. Within the framework of this first-ever structure, thirty French and Belgian researchers pursue the idea of modified nucleic acids, or fragments of DNA for diagnostic and therapeutic use.

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Nucleic acid (DNA, RNA) recognition is biunivocal and makes possible the conception of a probe modified by a metallic complex of photoactivated ruthenium.
After recognition occurs between the DNA/metallic complex and the target fragment of DNA or RNA, the the complex can be permanently damaged by luminous radiation, which will inhibit the biological action of the target.


Under the leadership of Jean Lhomme, the Biomolecular Engineering group at Grenoble's Joseph-Fourier University decided in 1996 virtually to do away with its walls in order to fuse with three laboratories of the Free University of Brussels2 and create an LEA* (European Associated Laboratory). Currently headed by Pascal Dumy, the LEA's objective is to pool resources and expertise in the pursuit of a common research aim as well as to promote student exchange.

Interaction between DNA and luminescent metallic complexes of ruthenium
The twin pillars of this "laboratory without walls" work together in a close and complementary way. French participants contribute their expertise in bio-chemistry and organic synthesis while their Belgian counterparts bring their understanding of metallic complexes of ruthenium and their physical chemistry implications. The LEA's study of intermolecular interactions, one of its most advanced research fronts, illustrates the complementarity perfectly. The goal of this project is to associate modified DNA with a luminescent metallic complex as a possible biomolecular tool for therapeutic purposes.
"In Grenoble we specialise in synthesising DNA molecules that have been chemically modified, while the Belgian group is particularly focused on the study of photon-matter interactions”, Dumy explains.

Synthesising and studying properties
In practice, the Belgian teams work on synthesising large metallic complexes that can be  photoactivated. The French researchers for their part are oriented toward modifying DNA and associating it with metallic complexes. The second stage of the project involves studying the properties of the new biomolecule thus formed, and here also the two branches complement each other. The French contribution is to carry out biological studies at the same time that their Belgian partners analyse the new molecule's photochemical and photophysical properties.

Towards biomolecules with therapeutic potential
The LEA scientists hope eventually to obtain a luminescent DNA molecule of therapeutic use, based on the association of DNA with a metallic probe, and which could inhibit the expression of target fragments of DNA or RNA. Such a family of molecules could also serve as a diagnostic tool, thanks to their luminescence, helping to detect nucleic acid sequences (in DNA or RNA) of therapeutic interest, within cells.


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Summary

à lire

"Photo-crosslinking in Ru-labelled duplex oligonucleotides." O. Lentzen, J.-F. Constant,
E. Defrancq, M. Prévost, S. Schumm,
C. Moucheron, P. Dumy, A. Kirsch-De Mesmaeker, ChemBiochem, 2003 4, 195-202.

Contact

Pascal Dumy
Laboratoire d'études dynamiques et structurales de la sélectivité (LEDSS)
E-mail: Pascal.Dumy@ujf-grenoble.fr

View web site
ledss.ujf-grenoble

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