PhD Studentship: Expanding the biological diversity of reactive fragments

Closing Date: 29 April 2024 at 23:59

Eligibility: UK Applicants only

Funding

EPSRC Doctoral Training Partnership Studentship offering the award of fees, together with a tax-free maintenance grant of £19,237 per year for 3.5 years. Training and support will also be provided.

Lead Supervisor’s full name and email address

Professor Adam Nelson – a.s.nelson@leeds.ac.uk

Co-supervisor name: Professor Richard Bayliss – r.w.bayliss@leeds.ac.uk

Project summary

Identifying and exploring new biologically-relevant chemical space is a major challenge, central to both chemical biology and medicinal chemistry. Access to high quality chemical probes dramatically influences the scope of experimentally-investigated biomedical science and is crucial for validating novel targets. With the advent of reactive fragments, and the powerful companion technology of chemical proteomics, we now envision the prospect of mapping biological coverage systematically in a native cellular context.

In this project, we will develop connective reactions that enable the one-pot, plate-based synthesis of diverse sets of distinctive reactive fragments (RFs). We will thereby prepare libraries of diverse reaction fragments in plate-based format which will be screened for chemical modification of target proteins e.g. specific protein kinases. Promising reactive fragments will be optimised via further rounds of plate-based chemistry. We will thus demonstrate that diverse RF sets can provide useful starting points for the discovery of covalent probes of specific target proteins.

The specific scientific objectives are:

1. To develop connective plate-based chemistries to access diverse distinctive RF sets. The student will develop and apply novel connective chemistries in the synthesis of diverse sets of RFs.
2. To explore the suitability of the new connective plate-based chemistry for securing starting points for the discovery of novel covalent probes. Arrays of ligands will be screened for protein modification (e.g. of a specific protein kinase) by mass spectrometry. The most promising ligands will be optimised through further rounds of plate-based chemistry.
3. To characterise optimised covalent ligands. We will harness a range of structural biology, biophysical and enzymology techniques to enable characterisation of the most promising covalent ligands that are discovered.

Entry requirements

First or Upper Second Class UK Bachelor (Honours) degree or equivalent

Subject Area: Organic Chemistry, Pharmaceutical/Mecidinal Chemistry

Keywords

Chemical Biology, Mass Spectrometry, Mecidinal Chemistry, Catalysis, Chemical Proteomics, Organic Synthesis

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