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

基于两个实验室在3个以前的学生之间建立的合作工作，该项目将建立对G-CSF生物分子的功能和稳定性至关重要的领域，集中在被确定为对3-D结构稳定性重要的区域（从计算机建模和疏水标记染料结合），以及与改善/受损生物活性相关的区域。这将继续扩大结构和形成对蛋白质在液态下聚集倾向的影响的知识基础，这些知识基础已经在Dalby教授的小组近年来为各种生物分子开发。然后将其外推并使用HDX质谱和2-D NMR与冻干状态进行比较，以确定类似的不稳定区域是否适用于干燥状态。这将为生物治疗药物的配方开发得出重要结论，这是一个关键领域，因为这组产品正在成为21世纪世纪制药市场的主导者。

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.