Tandem organocatalysis for the bi-functional modification of proteins

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.

Impact on the economy

Seven out of the top ten selling drugs worldwide are now biologics, but as a community we also know that the industrial/pharmaceutical pipeline of new potential treatments for a vast range of disease areas, is also dominated by macromolecule, or macromolecule-drug conjugates, with the market predicted to be worth over $20bn worldwide within 5 years. Novel strategies for synthesis of these bio-conjugates are therefore high priority for industrial leaders, and it is anticipated discoveries resulting from this project will have a significant impact on the development of new methods for chemical modification of proteins utilised by the global pharmaceutical companies working in this area, with further potential impact in personalised medicine, diagnostics, drug discovery, and vaccine development in the future.

Impact on society

Leishmaniasis is a parasitic infection, transmitted by sandflies, which afflicts over 12 million people in more than 90 countries across the globe. Following infection, leishmaniasis is treated with often-expensive antiquated toxic remedies, and there is currently no vaccine for this debilitating disease. One of the aims of this project is to develop new methods for constructing protein-small molecule fusions, which have vast potential as 'chemical mimics' of natural modified proteins integral to the life cycle of the Leishmania parasitic host, which have previously been used as vaccine candidates, but due to accessibility, only in their non-native unmodified form. Therefore, this project has the potential to make significant advances in treatment of a potentially fatal disease which infects over 1.3 million new people each year, and high quality research published in this field will therefore stimulate significant public interest in the area because it has a direct impact on quality of people's lives and health. During the project we will communicate our results with the public by using print and digital media, and exhibitions to emphasise the importance of improvements in the field of biologic synthesis and protein chemical modification, re-emphasising the roles organic chemistry and chemical biology can play in the development of new age protein based medicines.

Impact on people

The Department of Chemistry at the UofY is nationally renowned for its exceptional research output, but also for its inspirational teaching, exemplified by a commitment to include research driven scientific content in both undergraduate and postgraduate lecture courses. In a continuation of this philosophy, the student cohort at York will benefit from the research results arising from this project, through incorporation of outputs into lectures, and also shared with undergraduate research students on placement in the lab. Therefore, the impact of this research could be measured not only in its influence upon the existing team members in my lab, and other researchers already active in this field in the UK, but also upon new budding scientists.