Investigating bio-pharmaceutical aggregation one molecule at a time.

4 year BBSRC studentship, under the BRIC doctoral programme.
The successful applicant will receive fees and stipend (c.£13590 for 2013-14). The PhD will start in Oct 2013. Applicants should have, or be expecting to receive, a 2.1 Hons degree in Biochemistry, Chemistry, Physics or a related subjects. EU candidates must have been resident in the UK for 3 years in order to receive full support.
There are 2 stages to the application process. Please see our website for more information:
www.fbs.leeds.ac.uk/gradschool/keywords/mnuFindaphd.php

"A force-activated trip switch triggers rapid dissociation of a colicin from its immunity protein." Farrance, O., Hann, E., Kaminska, R., Derrington, S., Kleanthous, C., Radford, S. and Brockwell, D. (2013) PLoS Biol 11:e1001489



Protein drugs (bio-pharmaceuticals) offer advantages over conventional small molecule therapies but their development is challenging because many are prone to aggregation. The interaction surfaces that drive aggregation are, however, difficult to characterise yet this knowledge is vital to design sequences that are inherently amenable to bio-processing. The ability to generate inherently ‘developable’ candidates would reduce drug lead time, increasing the UK’s competitiveness in this sector.

Single-molecule dynamic force spectroscopy (DFS) methods present the opportunity to analyse aggregation-prone bio-pharmaceuticals at extremely low concentrations and to visualise the binding interface(s) that trigger aggregation. The aim of this project is to apply our expertise in DFS on protein complexes to provide new insight on the aggregation of Fabs supplied by our industrial partner on this project, UCB Celltech.

We have recently demonstrated (Farrance et al., 2013) that DFS can identify ‘binding hotspot’ residues key to binding affinity and therefore to aggregation propensity. This method measures the effect of a series mutations in one binding partner on the force required to dissociate the protein complex. It is analogous to the powerful phi-value analysis used to delineate protein folding mechanisms.

UCB Celltech is a key player in the burgeoning bio-pharmaceutical sector. The research will be carried out primarily in the Astbury Centre for Structural Molecular Biology, but will include visits of up to several months to UCB Celltech, to exploit the expertise and advanced technologies available there.