Luminescent Anion Receptors for High-Throughput Bioassays in Drug Discovery

The aim of this PhD project is to synthesise luminescent molecules that bind reversibly to target biological anions, which are produced during pharmaceutically important enzyme reactions. Anion binding to the molecular receptor will induce a luminescence response that enables measurement of enzyme activity in real time. The receptors will be developed into novel bioassays, enabling better selection and validation of new drug candidates at an early stage in drug discovery.

Full Project Detail Enzymes that consume and produce nucleoside polyphosphate anions (e.g. kinases) represent a major target in cancer drug discovery. Many drugs act by inhibiting enzyme activity; therefore, to increase confidence in the selection of lead drug compounds, it is crucial that pharmaceutical companies have robust assays to measure enzyme activity accurately. Most existing assays require expensive, unstable antibodies or chemically modified substrates, which are time-consuming to prepare and place a strain on the drug development process.

The aim of this project is to develop molecular probes that bind reversibly to specific nucleoside polyphosphate anions (e.g. ADP), which are produced during pharmaceutically important enzyme reactions. Upon binding to the anion, the probe will provide a luminescent signal that enables precise measurement of enzyme (e.g. kinase) activity in real time.

The molecular probes developed in this project will provide a vital step towards the rapid, accurate determination of enzyme kinetics and mechanisms. This would enable better selection and validation of new drug candidates at an early stage in drug discovery, reducing effort pursuing compounds destined to fail at the more lengthy and costly development phases. Strategies for promoting cellular uptake of the probes will be investigated to enable monitoring of biochemical processes in specific compartments of living cells.

To achieve this, we will explore how changes to the structure and geometry of the molecular probes affect anion binding selectivity and cellular uptake behaviour. This project is multidisciplinary in nature, spanning the areas of synthetic organic chemistry, supramolecular chemistry, and bioassay development. The student will gain excellent training in a range of techniques including organic synthesis, study of host–guest interactions using optical spectroscopy, bioassay development, and cellular imaging.

The student will be very well trained for roles in industry. Pharmaceutical and biotechnology companies increasingly require scientists with a combination of synthetic and bioanalytical skills. Therefore, there are many potential employability options for the student.

94% of Loughborough’s research impact is rated world-leading or internationally excellent. REF 2021