Metals in Biology - Inorganic Biological and Cellular Chemistry - Research

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Metals in Biology - Inorganic Biological and Cellular Chemistry

 

Research

 

a) Bio-active metal complexes: anti-oxidant Mn complexes, antibacterial agents


SODs are proteins protecting the cells against oxidative stress by dismutating superoxide. Their activity can be reproduced by low-molecular weight manganese complexes, called Mn SOD-mimics. Mn SOD-mimics can be used as antioxidant metallodrugs to rescue cells from oxidative stress. We wish to characterize the SODmimics activity and fate in cells. We have shown  that complex Mn1 (figure 1) efficiently reduces the flow in reactive oxygen species (ROS) in activated macrophages (coll. C. Amatore, F. Lemaître, M. Guille, UMR PASTEUR) [1a]. In collaboration with the group of medical doctors from LBM (team 4), we have investigated the effect in intestinal epithelial cells and shown Mn1 is efficient to reduce inflammation and to compensate for SOD under LPS challenge, known to mediate oxidative stress [1b].

An important question with regard to the bio-activity of metal complexes is their bio-availability: functionalization with peptides, such as cell-penetrating peptides studied by other members of LBM-Team 1 (peptides in biology) and also by LBM-Team 2  of LBM, is a way to improve bio-availability. 
We have recently funtionalized a series of Cu(II) complexes with peptides to enhance their anti-bacterial effect [2].

 

 

From Magritte, La clairvoyance



Figure 1

Bio-inspired SOD mimics:

allegory of bio-inorganic chemistry

and complexe Mn1

 

b) Metal-based probes and building blocks

 

b1. Metal-CO derivatives can be used as multimodal probes. We design and develop metal-based probes that we have named SCoMPIS for Single Core Multimodal Probes for Imaging (SCoMPIs). They are design to display multimodal spectroscopic features in a single molecualr core. Correlative imaging approaches were undertaken using these SCoMPIs involving fluorescent and vibrational imagings at the sub-cellular level [3]. Our group has pioneered the development of M-CO probes for sub-cellular IR-imaging [3-9]. These probes absorb IR-light in the 2000 cm—1 energy-range, which is the window of transparency in IR-range for biological samples. Vibrational imaging is an emerging technique and shows some advantages: low energies, no electronic excited state involved, no photobleaching, easy implementation from cells to tissues imaging, reliable quantification. As the IR-signature of a cell or of a tissue is a digital imprint of its status, IR-imaging of the SCoMPIs can be combined with structural IR-analysis of a cell or tissue. M-CO probes can be designed to be fluorescent, emissive in the visible (530 nm) after an absorption close to the visible range (350 nm), with a weak quantum yield but which is typical of metal-center probes and does not preclude imaging.

The SCoMPIs we develop can be easily conjugated to bio-molecules in order to track them in a biological environment [6, 10].

Because quantum yield depends on the environment, fluorescence is not appropriate for quantification. In contrast, IR enables reliable quantification as the IR-intensity of the signals from of the M(CO)3 does not depend on the environment [11].

We have acquired, in collaboration with physicist a strong expertise in IR-imaging, both using synchrotron –based IR-microspectroscopy (coll. C. Sandt, synchrotron SOLEIL) and a challenging technique, called AFM-IR, that couples an IR-laser with an AFM to record spatially resolved IR-map (in absorption) with a resolution close to 50 nm (coll. A. Dazzi, LCP, Univ-Paris-Sud 11). Recently, we have shown that it is poisble ti image those SCoMPIs in tissue (skin section) [10].

 

 

 

 

 

 

 

 

Figure 2

SCoMPI and bimodal imaging

 

(c) More generally, we are interested in the control of the chemical properties of metal-complexes by ligand modulation. Two directions have been explored recently: design of bis-Mn systems with a controlled Mn-Mn distance to measure distances in EPR (ANR project) [12]; design of ligand to control redox potential of Cu(II)/Cu(I) in favor of Cu(I) through an entatic process [13]; photophysical modulation in Re-complexes (14).

 

b2. Metal complexes as building blocks for various applications. Recently, in the frame of an ANR project with CEA (L. Tabares) and Frankfurt Univ. (T. Prisner), we have also developed recently Mn bimetallic complexes as unit to measure distance using dipolar coupling in electronic paramagnetic resonance. We have develop incremantable spacers to gradually increment the Mn-Mn distance and also genetically encodable dimeric Mn-complexes for further application in cell-biology.

 

Collaborations

C. Sandt (SOLEIL synchrotron) and A. Dazzi (Laboratoire de Chimie Physique, Univ. Paris-Sud 11): AFM-IR and IR-microspectroscopy
A. Vessières (Institut Parisien de Chimie Moléculaire, UPMC-Univ. Paris 06): M(CO)3 imaging
Z. Guéroui (PASTEUR, ENS): Fluorescence imaging
P. Seksik (INSERM, ER1157): Cellular models of oxidative stress
K. Crouse (Univ. Putra): peptides-functionalized antibacterial Cu(II) complexes
A. Baillet-Guffroy (Laboratory of Analytical Chemistry, Faculty of Pharmacy, University Paris-Sud)
B. Limoges and E. Anxolabéhère (Laboratoire d’Electrochimie Moléculaire, Univ. Paris VII)
T. Prisner, Frankfurt University and L. Tabares (CEA-France): Mn-complexes to measure distances in EPR

The group is member of the FrenchBIC, French network in bioinorganic chemistry: frenchbic.cnrs.fr.

 

Funding since 2005

-ANR contracts (French Research National Agency):
three as principal investigator (PI) (C. Policar; MAGIC-2016-2021; N. Delsuc ANRJCJC and H. Bertrand ANRJCJC 2016) and three as a partner (part.) (Take Care, PI M. Robert, 2011-13 ; Metabact, PI I. Artaud, 2011-13 and MnHFPELDOR, PI L. Tabares, 2012-2015)
-Paris-Sciences-Lettres contract structuration of research:
2015-16: PI C. Policar, INOCELLCHEM coll. With ESPCI (J. Vinh) and Institut Curie (S. Marco)
2016-2017: SUN, PI College de France (C. Aimé), part. ENS (N. Delsuc)
2016-2017: CATACARB, PI College de France (M. Fontecave), part. ENS (H. Bertrand) and ENSCP (F. Bedioui)
2017-2018: PINOT, PI Institut Curie (F. Mahuteau), part. ENS (H. Bertrand)
-Contract from Fondation pour la Recherche Medicale (FRM) 2016-2018, call Etudes Physico-chimiques innovantes pour la biologie et la médecine 2015 (PI C. Policar)
-Research fellowship from the Association François Aupetit (AFA) 2015-2017 (PI C. Policar)
-Since 2010, beamtime allocated on calls at SOLEIL (SIMS, DISCO and LUCIA beamlines) and at APS (N. Delsuc et C. Policar)
- Research contract CNRS-contract Interdisciplinary work (interface chemistry-physic-biology), support for risky research (2009), (PI C. Policar, coll. A. Dazzi, LCP, U. Paris-Sud and A. Vessières, ENSCP) 2009. Subcellular IR spectromicroscopy
-Starting grant (Action incitative jeunes chercheurs et jeunes chercheuses) (PI C. Policar) 2005-2008. Glycoligands and glycocomplexes

 

References

  • (1a) Bernard, A.-S.; Giroud, C.; Ching, H. Y. V.; Meunier, A.; Ambike, V.; Amatore, C.; Guille Collignon, M.; Lemaître, F.; Policar, C. Dalton Trans. 2012, 41, 6399.
  • (1b) Mathieu E.; Bernard A.-S.; Delsuc, N.; Quevrain, E.; Gazzah, G.; Lai, B.; Chain, F.; Langella P.; Bachelet, M.; Seksik, P., Masliah, J., Policar, C.; Inorg. Chem., 2017, 56, 2545-2555.
  • (2) Low, M. L.; Maigre, L.; Dorlet, P.; Guillot, R.; Pagès, J.-M.; Crouse, K.; Policar, C.; Delsuc, C. Bioconj. Chem. 2014, Accepted.
  • (3) Clède, S.; Lambert, F.; Sandt, C.; Gueroui, Z.; Plamont, M.-A.; Dumas, P.; Vessières, A.; Policar, C. Chem. Commun. 2012, 48, 7729.
  • (4) Clède, S.; Lambert, F.; Sandt, C.; Gueroui, Z.; Delsuc, N.; Dumas, P.; Vessières, A.; Policar, C. Biotechnology Advances 2013, 31, 393.
  • (5) Clède, S.; Lambert, F.; Sandt, C.; Kascakova, S.; Unger, M.; Harté, E.; Plamont, M.-A.; Saint-Fort, R.; Deniset-Besseau, A.; Gueroui, Z.; Hirschmugl, C. J.; Vessières, A.; Policar, C. Analyst 2013, 138, 5627.
  • (6) Dazzi, A.; Policar, C. In Biointerface Characterization by Advanced IR Spectroscopy Pradier, C.-M., Chabal, Y., Eds.; Elsevier: Amsterdam, 2011, p 245.
  • (7) Mattson, E. C.; Unger, M.; Clède, S.; Lambert, F.; Policar, C.; Imtiaz, A.; D'Souza, R.; Hirschmugl, C. J. Analyst 2013, 138, 5610.
  • (8) Policar, C.; Waern, J. B.; Plamont, M. A.; Clède, S.; Mayet, C.; Prazeres, R.; Ortega, J.-M.; Vessières, A.; Dazzi, A. Angew. Chem. Int. Ed. 2011, 50, 860.
  • (9) Clède, S.; and Policar C., Chem. Eur. J. 2015, 21, 942-958
  • (10) Clède, S.; Delsuc, N.; Laugel, C.;  Lambert, F.; Sandt, C.; Baillet-Guffroy, A.; Policar, C. Chem. Commun 2015, 2687-2689
  • (11) Clède, S.; Lambert, F.; Saint-Fort, R.; Plamont, M. A.; Bertrand, H.; Vessières, A.; Policar, C. Chem. Eur. J. 2014, 20, 8714.
  • (12) Ching,  V.H.Y.; Demay-Drouhard, P.; Bertrand, H.; Policar, C.; Tabares, L. C. and Un, S., Physical Chemistry Chemical Physics 2015, 17, 23368 – 23377
  • (13) Garcia, L.; Cisnetti, F.; Gillet, N; Guillot, R.; Aumont-Niciase, M.; Piquemal, JP.; Desmadril, M. ; Lambert, F.; Policar, C. J. Am. Chem. Soc. 2015, 137, 1141−1146
  • (14) Bertrand, H.C.; Clède, S.; Guillot, R.; Lambert, F.; and Policar, C. Inorg. Chem., 2014, 53, 6204−6223