The development of catalysts for the activation of small molecules, such as H2, under mild and environmentally friendly conditions is one of the most important challenges for chemistry. In this context, the use of Frustrated Lewis Pairs (FLP) chemistry as catalyst appears particularly appealing to solve this issue. This project aims to confine FLP-type systems in molecular cages and apply them to small molecule activation and catalysis. These systems will also be tested on more complex substrates, in order to test their efficiency on other key reactions in the chemical industry such as Baylis Hillmann or Mannich reactions. The originality of our approach, when compared to other FLPs systems, lies in the encapsulation of the Lewis acid or base (or both) in molecular cages (hemicryptophanes), this will lead to nanoreactors with well-defined cavities just above the acid / base partners. This cavity will not only avoid direct Lewis acid-base interaction, but should also induce new reactivities by imposing unusual conformations and orientation on the encaged reagents. Thus more efficient catalytic systems are expected because of the desolvation and "stress" of the substrate inside the cavity. Moreover, hemicryptophanes are chiral hosts and able to selectively recognize substrates, opening the way for asymmetric catalysis. Thus, the confinement of the catalytic site and the substrates in a single cavity should lead to a high catalytic activity and a high enantioselectivity. Furthermore, this project is based on a strong and constant interaction between theory and experience, in order to solve the important issues mentioned above.

Prokaryotes have evolved sophisticated strategies to regulate intra-cellular copper concentration since it is essential for cell survival to import copper and incorporate it at the active site of key enzymes, but a higher intra-cellular concentration is toxic. These copper-concentration regulation mechanisms can be insufficient in environments with high amount of copper, leading to cell death. This bactericidal property of copper has been exploited since the Middle Age and regains interest nowadays to substitute antibiotics. Besides, copper is also used by the immune system to eliminate pathogenic organisms. Nevertheless, how copper or copper complexes induces cell death is not understood. The ChapCop project aims at a better understanding at both the cellular and the molecular levels of the mechanisms responsible for copper-induced toxicity and the resistance strategies implemented by bacteria to resist to copper stress. This project is based on our recent preliminary results showing (i) that a high concentration of copper induces the denaturation of the stable structures of many proteins leading to the formation of protein aggregates and (ii) that some molecular chaperones are able to decrease copper-induced protein aggregation. Our working hypotheses is that molecular chaperones with structural zinc sites may play a major role in bacterial survival. Copper is likely to damage these zinc sites, leading to a structural transition enabling chaperone activation against copper-induced aggregation. Using Escherichia coli as a model, two main objectives will be pursued. 1- The relative impact of free copper or of various copper-complexes known for their anti-bacterial activities on protein aggregation will be determined. Copper-sensitive proteins that tend to aggregate under a variety of conditions will be identified as well as copper complexes with the most potent bactericidal effect. 2- The role of holdase chaperones in condition of copper stress will be assessed in vivo and in vitro on model proteins as well as on physiological clients, with a special focus on the Zn-containing holdases chaperones Hsp33 and DnaJ. The ChapCop project gathers five partners with complementary expertise in copper handling, (bio)chemical reactivity, proteostasis, and molecular chaperones. Our interdisciplinary approach relying on bioinorganic chemistry, microbiology, biochemistry and structural biology will provide major breakthroughs on the understanding of strategies dedicated to maintaining bacterial proteome integrity during toxic copper exposure and per se, will define the bacterial strategies to survive to copper-stress.

BattAllox aims at targeting multiple electron transfer and tuneable redox properties for enhanced energy storage systems. Using bioinspired design principles and molecular engineering, this project focuses on interfacing redox-active isoalloxazine and alloxazine units with coordination chemistry to deliver highly tuneable and versatile redox systems. Redox behaviour at the molecular and higher levels will be studied on small-molecule organic units, organometallic complexes and Coordination Polymers. These redox species will be the basis of a new class of robust multi-electron transfer materials, for electrode materials, for example, and will be incorporated in redox-flow batteries. This multi-scale and multidisciplinary approach bring together molecular design, electrochemical studies, coordination networks and redox-flow batteries.

Double-bond photoisomerization has long been exploited in man-tailored molecular photo-switches or light-driven molecular motors for opto-mechanical energy conversion and photocontrol of molecular functions. In such applications, a high photo-isomerization quantum yield (QY) is desirable to enhance the molecular device efficiency. However, no chemical design criterion has been rationalized to date for maximizing the photo-isomerization QY of synthetic molecules. Natural evolution instead has developed photosensory proteins, in which photoisomerization triggers biological functions with outstanding efficacy. A paradigmatic example is the rhodopsin (Rho) protein, the pigment for vision. In the PhotoMecha project, we will explore the mechanism of ultrafast C=C double bond photoisomerization of small synthetic, biomimetic photo-switches. These compounds have been designed to mimic the electronic structure – i.e. the potential energy surfaces (PESs) - of biological chromophores and shown to undergo an ultrafast C=C double bond photoisomerization similar to that observed in Rho. Like most photoisomerizing compounds, the QY of the biomimetic switches does however not exceed 30%, while it is 67% in Rho. Many theoretical predictions agree, that the PESs landscapes, their so-called “conical” intersection (CInt) and the vibrational motions at the CInt control the overall photoreaction QY. Here, we propose to use the unique set of biomimetic compounds as models to unravel the physico-chemical parameters that control the excited state decay at the CInt and thus the QY. Our strategy will be to engineer their microenvironment in a rational way, in order to fine-tune their photoreactivity. The example of Rho already demonstrates that such a tuning is possible and has a critical influence on the photoreaction dynamics and QY. Hence, we will extend the investigation of the existing biomimetic compounds (i) in the gas phase (ii) in solvents of various polarities and (iii) encapsulated in appropriate supramolecular cages. State-of-the-art experimental and theoretical approaches will be jointly employed, including ultrafast UV-Vis spectroscopy (Partner P1 = IPCMS Strasbourg), time-resolved XUV photoelectron spectroscopy (Partner P3 = ILM, Lyon), synthetic supramolecular chemistry (Partner P2=IPCMS, Strasbourg) and quantum chemical modelling (partners P4=ICS Strasbourg and P5=U. Siena, Italy).

The fast spread of multi-resistant microorganisms represents a threat to public health that urgently needs new therapeutic approaches less prone to the development of resistant strains. Our objectives are the design, synthesis and in-depth biophysical studies of new antimicrobial peptide-photosensitizer (AMP-PS) conjugates for synergistic and selective inactivation of pathogens. The chosen AMPs will selectively drive the porphyrinic PS inside the bacteria while near IR light excitation will destroy them by creation of reactive oxygen species (ROS), without inducing bacterial resistance or damage to host tissues. This photoinactivation approach provides a promising treatment for chronic skin and periodontal infections. Thus, an AMP-PS hydrogel will be developed for topical applications. A consortium of three partners specialized in peptide and porphyrin synthesis, biophysical and antibacterial studies, and design of biomaterials, will provide the skills and implementation necessary for the success of the project.