Site-selective functionalisation of peptides and proteins via free-radical-induced dechalcogenation

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The development of chemistry that enables researchers to decorate proteins at defined positions with a range of functional molecular 'tags' has the potential to generate significant scientific impact. The application of such techniques to the modification of protein-based 'biologic' drugs, a class that currently dominates the pharmaceutical market, facilitates the development of more effective treatments for disease. Within the context of fundamental science, the preparation of proteins that carry naturally occurring modifications provides tools to interrogate biological pathways and enable a greater understanding of cellular biochemistry. As a result, bioconjugate techniques are used routinely in academic and industrial labs across the world. This proposal describes the development of a novel and versatile approach to protein functionalisation that presents advances over current methods.Due to the characteristic chemical properties of proteins, synthetic methods that facilitate modification of these biological molecules must operate under a specific set of conditions. Successful bioconjugation reactions proceed in water at ambient temperature, afford high yield at low concentrations and demonstrate selectivity for one of the 21 naturally occurring (canonical) amino acid residues. Reactions that follow this template enable modification of a target protein without degradation of the amino acid sequence or the formation of undesired by-products. With these aspects in mind, we have developed a novel, efficient and selective reaction that can be tuned to target two natural amino acids; cysteine and selenocysteine. The method is rapid, quantitative and sustainable, proceeding under conditions ideal for protein chemistry. The protocol requires no precious metal catalyst or costly/unstable reagents and is operationally simple, allowing application across scientific disciplines to maximise impact within the chemical and biological sciences. This New Investigator Award will enable us to establish a multidisciplinary team focused on the development and application of our new synthetic platform. It is envisaged that a broad range of functionality could be installed into a protein of interest using this approach; the inclusion of contrast agents for medical imaging, drug-conjugates for therapy and reactive tags or natural protein modifications to facilitate the investigation of complex biological processes will be evaluated. Proteins modified with chemical groups that will enable further investigation of protein degradation and tools to target, image and treat highly invasive forms of cancer will also be delivered within the remit of this project. Furthermore, this collaboration will enable us to establish a base of expertise, technology, and training in protein bioconjugation within the School of Chemistry, University of Nottingham.The development of new, versatile chemistry that can be applied to install a range of functional groups into a protein, to suit many specific applications, would be a powerful addition to the methodology currently available to researchers.