ERC FUNDED PROJECTS

Histidine (His) is an ubiquitous ligand in the active site of metalloenzymes that is assumed by default to bind the metal center through one of its nitrogen atoms. However, protonation of His, which is likely to occur in locally slightly acidic environment, gives imidazolium sites that can bind a metal in a carbene-type structure as found in N-heterocyclic carbene complexes. Such carbene bonding has a dramatic effect on the properties of the metal center and may provide a rational for the mode of action of metalloenzymes that are still lacking a solid understanding. Up to now, the possibility of carbene bonding has been completely overlooked. Hence, any evidence for such His coordination via carbon will induce a shift of paradigm in classical peptide chemistry and will be directly included in basic textbooks. Moreover, this unprecedented bonding mode will provide access to unique and hitherto unknown reactivity patterns for artificial enzyme mimics. Undoubtedly, such a break-through will set a new stage in modern metalloenzyme research. A multicentered approach is proposed to identify for the first time carbene bonding in enzymes. This approach unconventionally combines the current frontiers of organometallic and biochemical knowledge and hence crosses traditional boarders. Specifically, we aim at probing carbene bonding of His by identifying reactivity patterns that are selective for metal-carbenes but not for metal-imine complexes. This will allow for efficient screening of large classes of metalloenzymes. In parallel, active site models will be constructed in which the His ligand is substituted by a heterocyclic carbene as a rigidly C-bonding His analog. For this purpose chemical synthesis will be considered as well as enzyme mutagenesis and subsequent carbene coordination. While such new bioorganometallic entities will be highly attractive to probe the influence of C-bound His on the metal site, they also provide conceputally new types of versatile catalysts.

1 249 808 €

Start date: 2008-07-01, End date: 2013-06-30

Anti-cancer immunotherapy has provided patients with a promising treatment. Yet, it has also unveiled that the immunosuppressive tumor microenvironment (TME) hampers the efficiency of this therapeutic option and limits its success. The concept that metabolism is able to shape the immune response has gained general acceptance. Nonetheless, little is known on how the metabolic crosstalk between different tumor compartments contributes to the harsh TME and ultimately impairs T cell fitness within the tumor. This proposal aims to decipher which metabolic changes in the TME impede proper anti-tumor immunity. Starting from the meta-analysis of public human datasets, corroborated by metabolomics and transcriptomics data from several mouse tumors, we ranked clinically relevant and altered metabolic pathways that correlate with resistance to immunotherapy. Using a CRISPR/Cas9 platform for their functional in vivo selection, we want to identify cancer cell intrinsic metabolic mediators and, indirectly, distinguish those belonging specifically to the stroma. By means of genetic tools and small molecules, we will modify promising metabolic pathways in cancer cells and stromal cells (particularly in tumor-associated macrophages) to harness tumor immunosuppression. In a mirroring approach, we will apply a similar screening tool on cytotoxic T cells to identify metabolic targets that enhance their fitness under adverse growth conditions. This will allow us to manipulate T cells ex vivo and to therapeutically intervene via adoptive T cell transfer. By analyzing the metabolic network and crosstalk within the tumor, this project will shed light on how metabolism contributes to the immunosuppressive TME and T cell maladaptation. The overall goal is to identify druggable metabolic targets that i) reinforce the intrinsic anti-tumor immune response by breaking immunosuppression and ii) promote T cell function in immunotherapeutic settings by rewiring either the TME or the T cell itself.

1 999 721 €

Start date: 2018-07-01, End date: 2023-06-30

With stellar masses in the range of eight to several hundreds of solar masses, massive stars are among the most important cosmic engines, each individual object strongly impacting its local environment and populations of massive stars driving the evolution of galaxies throughout the history of the universe. Recently, I have shown that stars more massive than 15 Msun rarely, if at all, form and live in isolation but rather as part of a binary or higher-order multiple system. Understanding the life cycle of massive multiple systems, from their birth to their death as supernovae and long-duration gamma ray bursts, is one of the most pressing scientific questions in modern astrophysics. To obtain the key observational breakthroughs needed to revolutionize our understanding of high-mass stars, my research program is developed along three themes: (i) investigate the physical processes that set the multiplicity properties of massive stars, (ii) establish the multiplicity properties of unevolved massive stars across the entire mass range, (iii) identify and uniquely characterize post-interaction products. The implementation of the MULTIPLES program involves ambitious time-resolved observational campaigns targeting large populations of massive stars at key stages of their pre-supernova evolution and in different metallicity environments. These campaigns will combine state-of-the-art spectroscopy and high-angular resolution techniques with novel multiplicity and atmosphere analysis methods appropriate for multiple systems. Upon completion, the observational constraints that will be obtained in this project will have implications that extend well beyond the sole domain of stellar astrophysics.

1 991 243 €

Start date: 2018-10-01, End date: 2023-09-30

The primary aim of this project is to substantially expand the frontiers of current benchmark organocatalytic technology by the design, preparation and evaluation of the first class of thiol-based nucleophilic catalyst capable of emulating the action of NAD+-dependant enzymes such as aldehyde dehydrogenases, which promote the chemoselective oxidation/reduction of aldehyde substrates under mild conditions in aqueous media. The proposed artificial enzymes are designed biomimetically (in the true sense of the word) – only careful examination of the core enzyme competencies, modes-of-action and active sites has guided the design process. One of the key issues which this proposal addresses is the inherent difficulty associated with the design of artificial cofactor-dependent enzymes due to the requirement for a) efficient recognition by the catalyst of both the substrate and the cofactor, and b) the exertion of control over their encounter in the active site. We intend to tackle this challenge by covalently attaching groups functionally equivalent to the catalytically active residues of aldehyde dehydrogenases to a rigid NAD+ analogue in a manner which allows for their synergistic and biomimetic cooperation. Structure determination/mechanistic studies and the application of these new catalysts in a range of oxidations/reductions (we envisage that this project will result in the first organocatalyst able to demonstrably promote either - depending on the reaction conditions), (dynamic) kinetic resolutions, desymmetrisations, and ligations) will be undertaken and the development of catalytic processes for reactions currently outside the scope of any catalytic methodology is a clear long-term goal. We also wish to pursue the application of this potentially groundbreaking nucleophilic catalytic technology (for which no efficient organocatalysts have been thus far reported) toward the selective synthesis of enantiopure building blocks and pharmaceutically relevant molecules.

1 249 772 €

Start date: 2008-10-01, End date: 2014-09-30