During the last decades, extensive work focused on the design of molecular systems displaying circularly polarised luminescence (CPL). A chiral light emitter shows different right- and left-handed circularly polarised emission which gives birth to CPL. CPL is key for the enhancement of CP-OLED screen brightness and was pointed as promising for bio-imaging. Therefore, designing systems displaying strong CPL emission and harnessing the produced CPL in devices applications are challenges that we aim to overcome. SupraCPL is a multidisciplinary project aiming at inducing or enhancing the CPL response of 3d complexes by a supramolecular approach. We will develop an innovative strategy, combining coordination complex emitters with chiral supramolecular environment to (i) induce CPL from an achiral chromophore (Cu(I), Cr(III)), or (ii) enhance CPL of chromium(III) chiral complexes showing record CPL for non-lanthanides. The originality of our approach comes from the chiral environment that will be provided by self-assembled capsules or cages structures enabling large effects and dynamic responses. First we plan to use emitting complexes as guests in chiral resorcin[4]arene or pyrogallol[4]arene hexameric self-assembled capsules. Then more complexity will be implemented using Cr(III) complexes as vertices of tetrahedral M4L6 cages. The latter cages are interesting platforms to be combined with CPL outcome for probing or controlling encapsulation by lock/unlock redox input. Therefore, we will finally implement NIR-CPL outcome in versatile applications inherent to cages architectures. To summarise, SupraCPL is an ambitious but realistic project that aim at generating or enhancing CPL in achiral or promising chiral emitters owing to supramolecular environment provided by capsules and cages. The strong CPL arising from this strategy will be valorised imputing CPL as new output in the molecular cages application fields like probing, substrate delivery or multicomponent dynamic systems.

In addition to their role in protein synthesis by the ribosomes, aminoacyl-tRNAs participate in various metabolic pathways as a source of ester-activated amino acids. Among the tRNA-dependent aminoacyl transferases, enzymes of the Fem family catalyze an essential step of peptidoglycan synthesis in pathogenic bacteria and are considered as attractive targets for the development of novel antibiotics. FemX, the model enzyme of the family, transfers L-Ala from Ala-tRNA to the epsilon-amino group of L-Lys in the peptidoglycan precursor UDP-MurNAc-pentapeptide (UM5K). The crystal structures of the apo-enzyme and of a UM5K-FemX complex have been determined but co-crystallization with Ala-tRNA has not been obtained. We propose to develop the semi-synthesis of highly modified aminoacyl-tRNAs and bi-substrates to explore the catalytic mechanism of FemX. We will synthesize chemical probes that will specifically interact with FemX and its substrates. Azides and alkynes will be introduced into the tRNA and in UM5K, respectively. The Huisgen-Sharpless Cu(I)-catalyzed cycloaddition reaction will afford bi-substrates containing the tRNA covalently linked to the peptidoglycan precursor. In parallel, the active center of FemX will be used to catalyze the same reaction. By this approach, we will obtain molecules suitable for co-crystallization with FemX. Because the in situ generated reaction products are likely to trap a single conformational state of FemX corresponding to the catalytically active form of the enzyme, this approach is likely to be more powerful than the conventional crystallogenesis screens made with the substrates or products of the reaction. Phospho-derivatives of the tRNA will be synthesized to mimic the putative tetrahedral intermediate resulting from the intramolecular nucleophilic attack of the carbonyl of Ala-tRNA by the vicinal ribose hydroxyl. These phospho-derivatives will also be used to trap a relevant conformation of the enzyme that allows the trans-acylation reaction of the amino acid between the 2’ and 3’ positions of Ala-tRNA to occur within the active site. The enzyme-catalyzed cycloaddition reaction will be further investigated both to identify inhibitors of FemX and to decipher the mechanism of the enzyme-assisted catalyzed cycloaddition reaction, which is poorly understood. We will assess and compare the contributions of substrate binding and substrate activation (i) in the CuI- and FemX-catalyzed cycloaddition reactions using the functionalized substrates, and (ii) in the amino acid transfer reaction catalyzed by FemX with the “natural” substrates. The information gathered on the catalytic mechanism of FemX and on the structure of its active site should provide the critical information for the rationale design of drugs active on Fem transferases from pathogenic bacteria such as methicillin-resistant staphylococci. The approach will be of broad application in RNA biology.

Thietanes stand out among other sulfur compounds as central scaffolds in many bioactive and natural products. They are also unequivocally recognized as highly valuable intermediates in organic synthesis. However, unlike the [2+2]-photocycloaddition of imines and, especially, carbonyl derivatives, the so-called thia-Paternò-Büchi reaction, which combines a photochemically excited thiocarbonyl compound with an alkene partner to form the thietane core, has received very scant attention and an enantioselective version of this transformation has not yet been reported in the literature. In this context, and based on very promising preliminary results, this collaborative research project APCP_TPB, resulting from a valuable combination of complementary French expertise, aims to develop visible-light promoted enantioselective thia-Paternò-Büchi reactions involving axial and planar chiral photosensitizers. Thanks to judicious designed binaphthyl- and [2.2]paracyclophane-based photocatalysts, this methodology will afford a sustainable synthetic access to a large diversity of highly valuable functionalized enantioenriched thietane derivatives. By combining the asymmetric version of this [2+2]-photocycloaddition with post-functionalization reactions of four-membered heterocycles into various photochemical domino sequences, diverse sulfur-containing heterocycles will be targeted. Finally, the high potential of these prepared chiral binaphthyl- and [2.2]paracyclophane-based catalysts will be demonstrated by their use in other photochemical and thermal innovative asymmetric transformations.

Medical applications in nanotechnology are a rapidly growing segment with significant impact on diagnosis and therapeutics for the treatment of human diseases. Nanoparticle (NP) based drug delivery is of particular interest as these materials may show prolonged circulation half-life, reduced non-specific uptake, and increased accumulation in specific tissues and organs through enhanced permeation and retention (EPR). Among the number of NP-based therapeutic approaches the delivery of an active compound by external trigger “on demand” and the intrinsic chemical and biochemical stimuli gated drug release are of particular interest. Nano-systems allowing “on demand” liberation are relying on stimuli responsive (also termed “smart”) materials triggered by pH, temperature modifications, variation of magnetic fields, or, light irradiation. Some of these methods can be applied in good spatio-temporal control, by which a high level of drug concentration (six- to ten fold) can be eventually attained. Although this strategy promises considerable advantages in term of reduced general toxicity and diminished resistance against the drug, the field is still in infancy: external activation of prodrugs with localized liberation of compounds stays a major challenge. The project describes the chemical part of a larger program that aims the design, synthesis and study of remotely controllable polymersomes for biomedical applications and wish to finalize the development of a novel class of multisite device applicable in term in therapy, deep within the body. Polymersomes have proven their utility to deliver therapeutic agents to specific tissues/organs with potential therapeutic and theranostic applications where the therapeutic delivery can be simultaneously combined with diagnostic capabilities. They are extremely stable and robust - often too stable - for efficient drug delivery. The present application suggests method for image-guided local activation. The use of double selecting criteria, such as biological uptake and site selective activation would result in considerable reduction of adverse effects of many chemotherapy treatments what is always of paramount importance. In the heart of this novel activation methodology lies a recently developed fragmentation reaction that is based on (local) electron-transfer reaction triggered by penetrating X-ray, or, gamma light; the method was patented, and optimizations for biomedical applications are actively pursued. The method allows X-ray-gated delivery of virtually unrestricted variety of compounds having therapeutic interest in otherwise unaccessible (body) spaces, with the ability to follow the distribution and the liberation in real time by different bioimaging modalities, with the potential for multimodality. The project suggests to test a series of new redox fragmenting elements with charge-neutral nanoparticles (NPs) as sensitizers. Iron oxide NPs are considered which are among the few nanomaterials that are nontoxic, bio-compatibles, approved for therapeutic use and can be imaged. We believe, that the proposed system have the potential in theranostic applications combining thus both the ability to deliver a drug on a controlled manner and to monitor its distribution. Although this application is limited to show the proof of principle of the concept, domains of potential biomedical applications can be foreseen, such as treatment of inflammation, drug abuse, where intracellular drug-delivery is needed and also in cancer therapy, minimizing the side effects of chemotherapy, and also where the major part of the required instrumentation is already implemented. Biomedical applications are only part of the potential field of interest, as the method may find application in microfabrication where 3D controlled manipulations in high spatial resolutions are needed in inaccessible spaces.

Today, there is a real revolution in therapeutic applications using or targeting nucleic acids (mRNA vaccines, antisense oligonucleotides (ASO) or siRNA). In addition, the role of RNA methylation and its diversity in human disease is emerging alongside that of DNA. The impact of DNA hypermethylation in certain cancers is well known, leading to the successful use of MTase inhibitors in leukaemia (AML). Deregulation of RNA methylation has been linked to the development of diseases such as cancer, and several pharmaceutical companies have focused their research on developing inhibitors of the METTL3/METTL14 complex, which catalyzes the N6 methylation of adenosine (m6A) of mRNA. More recently, it has been shown that RNA m6A modification plays a central role in the virus cycle. These methylations, introduced by the cellular methylase METTL3/14, which have various consequences on RNA structure, splicing, stability or translation, they enable some viruses to escape detection by the innate immune system, while they are detrimental for others. A preliminary study showed the importance of m6A modifications in the replication of influenza A virus (IAV), and proposed a global mapping of these modifications on IAV RNAs. However, this study failed to identify the pathways and mechanisms affected, notably due to the poor resolution of the mapping. So there are still numerous aspects that require further exploration.Our project proposes the parallel use of innovative experimental technologies and a statistical study of available sequences employing artificial intelligence to detect crucial viral RNA methylation sites for IAV replication and interspecies transmission. We will develop chemical tools that probe, inhibit or mimic these modifications in a context of viral infection. This will enable us to employ a chemobiological approach to identify the effects of m6A methylations on viral replication and production of infectious particles, the initiation of the innate immune response, and the metabolism of viral RNAs. Combining these results, we will experimentally determine the influence of methylation on the triggering of the innate immune response in various state-of-the-art cell systems, notably using both multicellular models of human lung epithelium in vitro and ex vivo models of murine and human lung tissue culture. We will then identify the cellular players involved by exploring the structural dynamics of RNA induced by methylation, by identifying the proteins bound to methylated RNA and, finally, by reverse genetics and designing mutant viruses. From a chemical perspective, this proposal aims to synthesize inhibitors of viral methyltransferases using novel and original scaffolds, designed through molecular modeling and validated through in vitro and in cellulo biological assays. This approach is expected to yield molecules with high selectivity and efficacy. Our multidisciplinary study will shed unique light on host-pathogen relationships, and we hope to define new therapeutic targets whose scope could extend beyond IAV viruses.