UMR 5182

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Chemical Biology and Biosensing

Our group performs research into the design and synthesis of small molecules for application at the nexus with biology.


Fluorogenic probes REsponding to enzyme activity

J.HaSSERODT

A major goal of J. Hasserodt’s research activities is the maturation of a line of imaging probes that depict enzyme activity with spatial resolution in biological samples, live cells and multi-cellular organisms. 

 

 

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His probes are built from three, sometimes four components and act as substrates for selected target enzymes. Enzyme turnover results in the release of a highly insoluble fluorophore that only fluoresces in the solid state. The usefulness of this approach has already been demonstrated in the tagging of live cells competent in the targeted enzyme activity. Currently, J. Hasserodt’s team seeks to demonstrate its usefulness for high-throughput screening of cell collections via cytometry (FACS). Research on the modification of each of the three components is ongoing so as to adapt the probes to further enzyme activities of interest in life and disease, and to optimize their physicochemical performance (response rate; emitted color; cell penetration efficacy; solubility).

 

 

Magnetogenic probes responding to enzyme activity

J. Hasserodt

 A second pillar of J. Hasserodt’s research consists in the development of a new line of molecular probes responding to specific enzyme activity (and other chemical analytes) by changing the electronic spin state of the probe.

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This requires the mastery of coordination chemistry in physiological media, and thus of the synthetic chemistry of poly-amine macrocycles and their complexation with iron(II) atoms. Samples containing the targeted enzyme activity pass from a non-magnetic (diamagnetic) state to a magnetic (paramagnetic) state, and the probe thus operates in a true off-on mode. The newly established paramagnetism can be detected by several established methods ranging from MRI instruments over EPR spectrometers and supra-conducting NMR spectrometers all the way to simple micro-NMR devices operating with a hand-held permanent magnet. Current research focusses on adapting the probes to operate at physiogical pH, optimization of response rate and cell internalization.

 

Xenon-cryptophane probes for MRI

 T. BRotin

The xenon-cryptophane complexes using hyperpolarized xenon have shown their high potential as contrast agents for MRI. Our group will pursue the design of xenon-cryptophane complexes for the detection of low concentrations of analytes or the association with proteins for in-vivo and in-vitro experiments. 

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The xenon-cryptophane complexes using hyperpolarized xenon have shown their high potential as contrast agents for MRI. Our group will pursue the design of xenon-cryptophane complexes for the detection of low concentrations of analytes or the association with proteins for in-vivo and in-vitro experiments. We aim at developing in-vivo experiments with small animals, which remain a difficult challenge. The production of fair quantities of molecules appears as one of the main challenges in this project. Works are already underway to provide cryptophane-biosensors in larger amounts. The development of xenon-biosensors is a collaborative work with two teams at the CEA Saclay for the MRI experiments and the production of hyperpolarized 129Xe gas. For instance, the detection of the internalization process of the transferrin protein in living-cells is an interesting example that will be further developed over the forthcoming period. New water-soluble biosensors will be synthesized to bind the transferrin protein without interacting with cell membranes. We will also focus our efforts on the synthesis of new water-soluble cryptophane biosensors attached to a RGD peptide for the detection of integrin protein in living cells.

The concept of xenon-complexes for biosensing (in particular for MRI applications) is indeed a very active field of research, and several groups are competing to provide effective cryptophane-based biosensors for the early detection of diseases or biological events. The main objective of our group is to keep the leadership in the domain. This can be achieved through our own skills in the synthesis of molecular cages and our strong collaborations with the recognized specialists in the production of hyperpolarized xenon and in NMR technology for medical imaging.

 

Inhibitors

 P. Maurin

Design and synthesis of potential inhibitors of HIV-1 integrase : this project in collaboration with theoretical chemists, biologists and cristallographers aims to develop (conception synthesis, and biological evaluation) a new class of inhibitors of the HIV-1 integrase with a different and complementary (oligomerisation inhibitors) mode of action than the only inhibitor available (Raltegravir) approved by FDA that is active against the strand transfer step.