Characterising protein-excipient interactions for improved biopharmaceutical formulation

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. Measurements will examine the effects of excipients on weak protein-protein interactions, protein aggregation and protein conformational stability. This will be combined with computational studies to 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. The project will be closely aligned with industrial formulation groups, and feedback from the target community will be readily available. The project will fit into a larger grouping at Manchester that works within biotechnology, including synthetic biology, and the advent of models to predict how small molecules can be used to solubilise proteins is timely.
This research targets the key aim of improving processing (and formulation) for biologics. Formulation, including the effects of small molecule interactions with a biologic, is critical since it also constrains bioprocessing upstream from the formulated product. The work also exploits new ways of working, seeking to contribute to the next generation of computational and bioinformatics tools. In terms of core science and generic professional skills, biological and chemistry/engineering approaches to industrial biotechnology are at the heart of the project.