Tandem organocatalysis for the bi-functional modification of proteins

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This first grant will help to establish a new multidisciplinary 'chemical biology' team within the Department of Chemistry at University of York, UK, focused on performing synthetic chemistry on proteins. The ability to selectively modify and subsequently harness and even tune the biological properties of macromolecules like proteins and enzymes using synthetic chemistry has heralded a revolution in the worldwide pharmaceutical industry, and the associated field of chemical biology. For example; seven out of the top ten selling drugs worldwide are now 'biologics' (i.e. complex proteins, macromolecule combinations, often decorated with small organic moieties), which are constructed using rapidly developing "bioconjugation" methods, as opposed to only a decade ago when this list was made up solely of small molecule drugs. Increasingly proteins are also modified by chemical ligation with small molecule tags with function enhancing properties for use in both industry and academia. Examples include conjugation of compounds such as polyethyleneglycol (PEG) to improve the half-life of probes and therapeutics; attachment of fluorescent and spectroscopic probes for in vivo imaging and tracking of macromolecules; and construction of proteins bearing 'mimics' of native in vivo modifications, which have played a role in the development of lead compounds for treatment of tropical parasitic diseases. Despite the obvious utility of these constructs however, there are limiting technical challenges facing chemists focusing on the 'bioconjugation' of macro/small molecule fusions, most notably the strive to achieve chemoselectivity- that is the ability to modify only one specific site on a protein backbone selectively in the presence of many others. This struggle is compounded by the fact that these new age synthetic challenges cannot be approached in the same way as the synthetic organic community has approached the synthesis of small molecules and natural products in the past- primarily using chemistry pioneered in organic solvents in a fumehood, often at elevated temperatures, at high concentration and in the absence of detrimental contaminants. Instead, bioconjugations using proteins must often take place in water, at neutral pH, at dilute concentration, and in the presence of a smorgasbord of chemical functionality present within the amino acid backbone of the protein itself. It is a necessity therefore, that new methods for the chemical modification of proteins which take place under these biologically compatible conditions continue to be developed in order to meet the ever-increasing demand for proteins with modulated function and utility. In this project we aim to contribute to this innovation drive for new protein bioconjugation methods, while also establishing a new paradigm for bioconjugation by redefining the chemistry of an unfashionable and oft forsaken protein motif and subsequently developing a new tandem strategy for the chemical modification of proteins using chemistry enabled and under the control of small molecule catalysts. We will then showcase the utility of this method in a collaborative chemical biology study of direct therapeutic relevance.