Inorganic complexes are increasingly used for biological applications, as metallodrugs or metalloprobes. We aim at going from chemistry in round-flasks to cells. We use the metal complexes that we design in cells for therapeutic applications or as probes, in connection with oxidative stress.
On the one hand, we work on the design of metalloprotein mimes with antioxidant activity, which we are studying in cells, mainly human cells relevant in the context of different pathological situations. On the other hand, we prepare metallic systems, which can be used as probes for unconventional imaging (infrared or X-ray fluorescence). We are also working on redox homeostasis and we develop tools for the quantification of hydrogen peroxide, in link with tissue regeneration and morphogenesis.
Most of the metal complexes studied in the literature for their bioactivity are used as anticancer, antibacterial, or antifungal agents. Most bioanalyses focus on their toxicity towards cancer cells, or micro-organisms. In contrast, the anti-oxidants we develop must be non-toxic and restore the basal activity in cells under oxidative stress and the probes are meant to minimally affect the cells. Their characterization requires the development of specific non-routine strategies and protocols to evaluate them.
We combine analyses of the bio-activity (what the complexes do in biological environment?) with analyses of the speciation (what is the active species?), determination of the quantities in cells (how many?), and imaging (where?).
(a) Bio-active metal complexes:
We design metal-complexes as mimics antioxidant metalloproteins, to be used to rescue cells from oxidative stress. We study them in cellular models of oxidative stress.[1,2] Some are non-peptidic-based complexes directly bio-inspired from the antioxidant superoxide dismutase,[1,3,4] and recently, we have been playing with inertia to improve stability in the cell environment. In a second strategy, we develop a combinatorial approach to design peptide-based complexes screened for their antioxidant activity.[5,6] In a third approach, in collaboration with Vince Pecoraro (Michigan univ.), we use three-helices bundles to design de novo proteins and study their anti-superoxide activity.
We study SOD mimics in the context of reduction of side effects of anti-cancer drugs, such as oxaliPt.
This work goes with the development of new analytical approaches. In particular, recently, in collaboration with an institute in Pau (IPREM) and in Paris (ESPCI-PSL university), we have shown that ionic mobility can be used for characterizing the speciation of low molecular weight complexes in cell lysates.
(b) Metal-based probes
Re(CO)3 complexes are developed as multimodal probes to correlate fluorescence, IR-imaging and X-fluorescence imaging. These probes are easy to conjugate to any kind of bio-molecule,[11–13] that can be imaged both by IR, possibly with a subcellular resolution using a near-field detection (AFM-IR), and by X-fluorescence.
A mitochondrial tracker for X-fluorescence imaging has been recently designed by the conjugation of a tris-phenyl-phosphonium by a Re-tris(CO) moiety.
(c) Redox Homeostasis: from cell to zebrafish
Tissue repair and embryogenesis both involve variations in H2O2 levels. The team works in zebrafish, which is a transparent organism in which optical probes can be followed. Tracking H2O2 levels in zebrafish expressing a genetically encoded H2O2 probe (Hyper) is possible, on the left at the scar of a severed fin and on the right in an embryo. In particular, we study the role of redox signaling during regeneration in adult zebrafish: the figure shows the distribution of H2O2 with an increasing concentration gradient towards the scar. H2O2 distribution also varies during morphogenesis, with waves in time and space.
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Bio-inorganic chemistry, metals in biology, Mn-SOD mimics, metal-based catalytic anti-oxidants, catalytic drugs, enzymes mimics or mimetics, sub-cellular imaging, metal carbonyles as multimodal probes (SCoMPIs standing for single core multimodal probes), IR-imaging, modulators of protein-protein interactions, optogenetics, redox control of protein traffic, cell plasticity in development and disease