Dr R Curtis, Prof Jim Warwicker, Prof P Popelier
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
About the Project
The study of small molecule (pharmaceutical) complexation with proteins has been embedded within drug discovery pipelines. In contrast, the interactions between small molecule excipients and protein therapeutics (biologics) are poorly understood, and yet the ability to formulate stable biologic solutions is critical for delivery to patients. Weaker binding of excipients relative to small molecule drugs explains a large part of this discrepancy. Increasingly though, experimental methods that report on weak interactions are being employed in industrial formulation and academic groups. The physical chemistry of interactions remains the same be they strong or weak, although the balance may change (i.e. for excipients, away from the detailed steric complementarity of small drug molecules). The current project aims to provide a first framework for biologic-excipient interactions, integrating computational and experimental studies. RC’s group is expert in measuring the effects of excipients on weak protein-protein interactions, protein aggregation and protein conformational stability. The groups of JW and PP computationally characterise protein and small molecule features that can be used to study complementarity and complexation. Allied to the data available in the protein structural database, the student will work to form a predictive model, benchmarked against structural data and iteratively tested with the student’s own experimentation. RC and JW collaborate with industrial formulation groups, so that feedback from the target community is readily available. A larger grouping at Manchester works within biotechnology, including synthetic biology, and the advent of models to predict how small molecules can be used to solubilise proteins is timely.
http://personalpages.manchester.ac.uk/staff/j.warwicker/
http://www.qct.manchester.ac.uk
Funding Notes
Applicants should have or expect to achieve at least a 2.1 honours degree in biochemical engineering, chemical engineering, bioengineering, biochemistry, chemistry (physical, analytical, or macromolecular chemistry), biophysics, pharmaceutical, biomedical or life sciences or related discipline.
The funding for this 4 year project covers fees at the Home student rate and enhanced annual stipend in excess of the Research Council minimum of £14,296 per annum through the UCL-EPSRC Centre for Innovative Manufacturing in Emergent Macromolecular Therapies.
References
Chaudhuri R, Cheng Y, Middaugh CR and Volkin DB. High-throughput biophysical analysis of protein therapeutics to examine inter-relationships between aggregate formation and conformational stability. (2014) AAPS J 16:48-64.
Elvin JG, Couston RG and van der Walle CF. Therapeutic antibodies: market considerations, disease targets and bioprocessing. (2012) Int J Pharm 440:83-98
Green AJ and Popelier PL. Theoretical prediction of hydrogen-bond basicity pKBHX using quantum chemical topology descriptors. (2014) J Chem Inf Model 54:553-61.
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