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

基于两个实验室在之前3个学生期间建立的合作工作，该项目将建立对G-CSF生物分子功能和稳定性至关重要的区域，重点关注对3- d结构稳定性至关重要的区域（从计算机建模和疏水标记染料结合），以及与生物活性改善/受损相关的区域。这将继续扩展结构和形成对蛋白质在液体状态下聚集倾向的影响的知识库，Dalby教授的团队近年来已经为各种生物分子开发了这种知识库。然后使用HDX质谱法和二维核磁共振进行外推，并将其与冻干状态进行比较，以确定干燥状态下是否存在类似的不稳定区域。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，因为这类产品正在成为21世纪制药市场的主导力量。

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.