Today, chemists know how to manipulate all kinds of molecules in their reaction flasks. In a biological environment, the case is quite different. However, the selective binding or release of molecules in the body could result in major advances in medicine, particularly in drug delivery or imaging. This is the objective of a new discipline called bioorthogonal (or biocompatible) chemistry. This highly selective chemistry makes it possible to carry out unnatural reactions in the blood, inside the cells, or even within a living organism. These new tools have already made it possible to develop powerful and useful binding technologies, which can be used for the preparation of bioconjugates derived from biomolecules and chemical compounds. This is what is known as "click" chemistry, a term that brings to mind the assembly of molecules. In contrast, very few bioorthogonal bond-breaking reactions (of the "release" type) have been described to date.
Chemists from the Institut des sciences du vivant Frédéric-Joliot have discovered that certain compounds, called iminosydnones, are able to rapidly react in biological environments with cyclic alkynes to form two new products: one from the binding of the two reaction partners, the other from a fragmentation of one of the two partners (Figure 1). They demonstrated that this reaction makes it possible to selectively label and purify a protein present in a very complex biological environment (e.g. liver extract).
How will "click and release" chemistry change the tools in the health sector? "There are many applications, mainly for therapy and imaging", replies Frédéric Taran, a researcher at the Institut des sciences du vivant Frédéric-Joliot, and the final author of the publication. "For example, targeted therapies involve binding a drug to an antibody that recognizes its target. It could be possible to inject a reagent to break the bond between the drug and the antibody once the target has been reached, so that the drug can have its effect. Work with the University of Strasbourg and the company Syndivia has demonstrated this functionality in blood samples." In imaging, this chemistry could be used to mitigate the drawbacks from the short life span of radioactive fluorine atoms commonly used in positron emission tomography (PET). Indeed, the association of an antibody with fluorine can take several days to reach its target, at which point the fluorine is no longer visible. The "click and release" solution would allow the radiotracer to be injected a few days after the injection of the antibody, and to bind the two at the desired moment.