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Performing chemistry within the cell

​Researchers from the CEA-IBITECS in collaboration with a team from the University of Strasbourg (UDS) have developed new reagents known as “chelating azides”, which can rapidly and selectively couple to any compound equipped with an alkyne group. The reaction can take place in any environment, including within a cell. These results were published as a VIP (Very Important Paper) on the website of Angewandte Chemie International Edition.

Published on 6 May 2014

Bio-orthogonal chemistry refers to a set of artificial reactions that can take place in a living organism, without interfering with its own biochemical activity. This allows, for example, following the fate of a substrate of interest (a metabolite, enzyme inhibitor, drug, etc.) inside the cell. The first step of the procedure is to modify the substrate by grafting to it a functional chemical group that does not affect its biological activity, before introducing it into the cell. Next, a probe complementary to the functional group is introduced that will react in situ with the latter and thus label the substrate that is to be followed. The coupling between an azide (on the probe) and an alkyne (on the substrate), two non-natural chemical functions, is one of the most commonly used bio-orthogonal reactions. However, this poses a problem since the reaction is catalyzed by copper, a cytotoxic metal, which limits its use in living cells.

Chemists from the CEA-IBITECS, with their colleagues from the UDS, have resolved this problem by creating a family of compounds combining a copper chelator1 agent (enclosing a single metal atom) with an azide function. Provided with a marker, such a compound can be used as a probe for binding to any substrate of interest to which an alkyne group has been grafted. Thanks to these “chelating azides” the reaction can proceed in the blood or within a cell, in a non-toxic manner and as fast as in a simple environment (the coupling occurs in less than thirty seconds).The scope is immense, ranging from medicinal chemistry (assembly of drugs for therapeutic antibodies, etc.) to imagery (tracers based on 64Cu) to pharmacology (drug monitoring).

[1] A ligand capable of binding a metal ion, in the manner of a pliers

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