Evolving natural peptide scaffolds for pharmacological tools and therapeutics
Ion channels and GPCRs are high-value drug discovery targets. However, achieving selectivity between closely related isoforms using small molecules remains challenging. Alternative antibody biologics bind a larger epitope and achieve higher specificity but have limited success in inducing desirable modulatory effects against membrane proteins with small extracellular loops. In contrast, natural toxin peptides can ensure high specificity and strong functional effects, having already proven themselves to be potent and selective modulators of ion channels and GPCRs[1,2]. However, many such peptides possess intricate arrangements of stabilising disulphide bridges which constitute a barrier to production from recombinant cell expression platforms due to disulphide scrambling causing misfolding. Chemical synthesis is used for accurate production but is slow, expensive, and inaccessible. Facile recombinant production would be a considerable advantage for broad accessibility and engineering. This project will explore a strategy to overcome this limitation. A Nav channel bait, already developed in the Miller lab, who have proven experience in membrane protein antigen production for generating protein binders, will be used to enrich for high expressing toxin peptide scaffolds expressed on yeast. The student will test peptides at Astra Zeneca (AZ) for functional effects on NaVs supported by Dr Liz Roberts, Senior Director Mechanistic Biology and Profiling. There will be the opportunity to then understand the molecular basis of actions by electron cryo-microscopy.
For more detailed project info and how to apply please see:
https://bbsrcdtp.lifesci.cam.ac.uk/available-icase-projects
Should you wish to discuss this opportunity further please contact Dr Miller (pm676@cam.ac.uk).