BIOCHEMLIG · Bio-Orthogonal Chemo-Specific Ligation

Bio-Orthogonal Chemo-Specific Ligation

Novel chemical tools are needed to dissect biological functions following the advances in molecular biology and biomedicine. Ligation reactions are central chemical tools for combinatorial library synthesis, supramolecular synthesis, the construction of peptidomimetics and glycomimetics, and for the labelling of biomolecules. The objective of the BioChemLig network is to diversify the portfolio of ligation reactions that fulfil the stringent criteria needed for in vivo applications, such as favourable kinetic profiles under high dilution, physiological compatibility and bioorthogonality. During the 48 months of BioChemLig project, we studied the identification of reactions based on: i) on the principle of the atom economy, effectiveness, simplicity, and broad applicability, ii) on the principle of environmentally benign “on water reactions”, iii) on the development of new artificial metalloenzymes and dendrimers, iv) on high throughput reaction screening, v) on protocol optimization via chemoinformatic tools, vi) on their use in designing novel biomarker tools. The consortium prioritises the most environmentally friendly, easiest and versatile new ligation methods. The network’s results have been disseminated to the scientific community through a total of 18 papers (so far, some paper are being submitted), 35 posters and 16 oral presentations . Also, 3 patents have been applied based on the work of the consortium fellows. The network’s progress is also updated on the website www.biochemlig.eu Throughout this project's second period, several workshops have be provided to our fellows to improve their scientific and "soft" skills, making them more adapted for the academic and private fields. Also, 7 fellows have chosen to take secondments opportunities within the consortium. The project scientific advances encompass discoveries in extending and bioorthogonal ligation methodologies, new progresses in the field of 18F labeling and novel analytical tools. Research highlights include advances in metalloenzyme and fluorination chemistry. Artificial metalloenzymes are composed of a catalytically competent organometallic moiety within a macromolecule. To improve the targeting specificity of anti-cancer metallodrugs; we investigated the formation of metallodrug mediated ruthenium piano-stool complex with the presenter protein and DNA. The assemblies bound more strongly to telomere G-quadruplexes than to double stranded DNA. We propose that the rational targeting of metallodrugs using presenter proteins could be exploited to improve their binding specificity to macromolecular targets. Also artificial metalloenzymes have been developed for olefin metathesis. A biotinylated Hoveyda-Grubbs catalyst incorporated within (strept)avidin affords artificial metalloenzymes for the ring-closing metathesis of N-tosyl diallylamine in aqueous solution. The network is also exploring new reactions that can be applied to imaging, such as fluorination reactions that can be used as 18F-labeled radiotracers for positron emission tomography. We have developed a palladium-catalysis method for the formation of allylic C_F bonds from allyl pnitrobenzoate, including “hot” fluoride. This method is significant, as halides are typically categorized as unsuitable nucleophiles for transition metal catalyzed allylic substitution. To our knowledge, this work demonstrates for the first time that 18F_C bond formation is feasible using a mild and rapid palladium-based protocol. The final results of the BioChemLig project includes the development of novel protein labelling and bioorthogonal reactions, in addition the scope of reactions investigated the ability to create bioimaging tools. In addition, two biosensors applications have also been developed in the network, which has enable the rigorous analysis of biological samples. More details can be found on the project website : http://www.biochemlig.eu/ Main contacts: Dr Rachid Baati, Coordinator, University of Strasbourg, France (rachid.baati@unistra.fr) Sandrine Carrière-Schott, administrative officer at the European department, University of Strasbourg, France (sandrine.schott-carriere@unistra.fr)

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