Mapping functionally important and stabilising regions in biotherapeutic proteins - GCSF as a model

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Building on the collaborative work established between the two laboratories over 3 previous studentships, this project will establish the areas critical to function and stability for the G-CSF biomolecule, concentrating both on regions identified as important for 3-D structural stability (from computer modelling and hydrophobic marker dye binding), and those linked to improved /impaired biological activity. This will continue to expand the knowledge base of the impact of structure and formation on the propensity for protein to aggregate in the liquid state, already developed in Prof Dalby's Group over recent years for a variety of biomolecules. This will then be extrapolated and compared to the freeze-dried state using HDX Mass spectrometry and 2-D NMR to establish whether similar regions of instability apply in the dried state. This will lead to important conclusions for the formulation development of biotherapeutics, a critical area as this group of products are becoming the dominant player in the 21st Century pharmaceutical market.