Covalent stereoprobes: Chemical tools for biomedical discovery

About the Project

This project will integrate high throughput experimentation and chemical proteomics to discover and optimise novel classes of covalent stereoprobes for elucidating biomedical mechanisms.

Bioactive small molecules continue to dominate our ability to treat disease (as drugs), and to enable understanding of biological mechanisms (as chemical probes). Chemical probes have been shown to have a transformational effect on the biomedical science that is investigated, and can help address the historically uneven exploration of protein biology. Covalent probes (i.e. that modify proteins), combined with proteomic technologies, are of particular value for discovery biomedicine, and covalent drugs have enjoyed a recent renaissance. Crucially, chemical probes can bridge discovery and translational biomedicine by: illuminating disease biology in native contexts; clarifying mechanisms of drug candidates; and unlocking new therapeutic opportunities.

Covalent stereoprobes are enantiomerically pure probes that form covalent links to their target proteins; the enantiomeric probe has identical physicochemical properties and can serve as a control.  Covalent stereoprobes can provide invaluable insights into biomedical mechanisms through e.g. context dependent protein modification or targeted protein degradation. However, current sets of covalent stereoprobes are very small and necessarily lack chemical diversity. This project will focus on the development of high throughput methods for the discovery or covalent stereoprobes, and will exemplify them in the elucidation of biological mechanisms.

The specific objectives of the PhD project are:

1. To establish methods for the high-throughput discovery of stereoselective protein modifiers.
   The student will develop methods for the plate-based synthesis of arrays of candidate stereoprobes from building blocks. A direct-to-biology approach will be used to discover stereoprobes that stereoselectively modify target proteins.
2. To discover and optimise covalent stereoprobes that modify a specific protein.
   An iterative, high-throughput approach will be used to discover and optimise covalent stereoprobes for a specific target protein (such as Aurora A kinase). Validation will involve resynthesis of promising compounds, and confirmation of stereoselective labelling.
3. To exemplify the value of covalent stereoprobes in discovery biomedicine.
   Finally, we will use optimised stereoprobes to elucidate the biology of their target protein. We will focus on alkynylated stereoprobes whose cellular targets can be profiled using chemical proteomics.

Funding Notes

A highly competitive EPSRC Doctoral Landscape Award Studentship, based in the School of Chemistry, providing the award of full academic fees, together with a tax-free maintenance grant of £21,805 per year for 3.5 years. Training and support will also be provided. This opportunity is open to UK applicants only. All candidates will be placed into the EPSRC Doctoral Landscape Award Studentship Competition and selection is based on academic merit.