Expediting glycosaminoglycan synthesis: expanding frontiers for carbohydrate chemical biology

这个UKRI奖学金将支持我在基尔大学发展新的科学专业知识，将化学和生物学结合起来。这项研究的首要目标是开发一种有效的技术来提供生物学上重要的碳水化合物。具体来说，一类低聚糖（其中多个碳水化合物单体连接在一起形成一条链）称为硫酸乙酰肝素。硫酸乙酰肝素是生物学中非常重要的调节剂，介导包括癌症、阿尔茨海默病、病毒感染如HIV和HSV以及许多细菌感染在内的病理状况。因此，有一个真实的需要询问和从根本上了解硫酸乙酰肝素在这些过程中发挥的生物作用。这将使科学家能够制定硫酸乙酰肝素介导的结构-活性关系的精确图片，并开始为他们控制的病理生理学开发新的治疗方法。硫酸乙酰肝素的化学合成特别具有挑战性，并且传统上总是使用溶液相反应完成。虽然在这一领域已经取得了显著的成就，但实现这种“全”合成所需的时间和资源是巨大的，必须找到更有效的方法。这一挑战将通过使用基于机器的合成自动化硫酸乙酰肝素生产来解决，然后用酶修饰获得的材料以安装使其具有生物功能的特定功能。这样的方法将彻底改变我们获取这些材料的速度，这对于研究和了解它们无处不在的调节生物学是绝对必要的。在进行这项研究时，我将采用多学科方法，包括传统有机化学、不断发展的合成自动化领域和化学酶修饰的创新领域之间的融合。这种组合将有助于开发更快，更环保的生物相关硫酸乙酰肝素方法，并克服目前在构建生物重要碳水化合物方面面临的挑战。这是一个迅速发展的全球性领域，目前在英国科学中代表性不足。本奖学金期间开发的技术和知识所提供的重要材料将用于探索这些疾病的机制，并帮助设计和开发针对它们的新疗法。

This UKRI Fellowship will support my development of a new scientific expertise at Keele University which interfaces chemistry and biology. The overarching goal of the research is to develop an efficient technology to provide biologically important carbohydrates. Specifically, a class of oligosaccharides (where multiple carbohydrate monomers are linked together to form a chain) called heparan sulfates. Heparan sulfates are very important regulators within biology, mediating pathological conditions including cancer, Alzheimer's disease, viral infections such as HIV and HSV and numerous bacterial infections. Therefore, there is a real need to interrogate and fundamentally understand the biological role that heparan sulfate plays in these processes. This will allow scientists to formulate a precise picture of heparan sulfate-mediated structure-activity relationships and initiate the development of new treatments for the pathophysiologies that they control. Chemical synthesis of heparan sulfates is particularly challenging and has traditionally always been completed using solution-phase reactions. Whilst there have been significant achievements in this field, the time and resource required to enable such 'total' syntheses is vast and more efficient methods must be found. This challenge will be addressed by automating heparan sulfate production using a machine-based synthesis and then modifying the materials obtained with enzymes to install specific features that enable their biological function. Such a methodology would revolutionise how quickly we can access these materials, which is absolutely necessary to study and understand their ubiquitous regulatory biology.In undertaking this research, I will adopt a multidisciplinary approach consisting of a fusion between traditional organic chemistry, the evolving field of synthesis automation, and the innovative field of chemoenzymatic modification. This combination will facilitate the development of a faster and greener approach to biologically relevant heparan sulfates and overcome the current challenges presented in the building of biologically important carbohydrates. This is a rapidly evolving worldwide field which is currently underrepresented in UK science. The important materials provided by the technology and knowledge developed during this Fellowship will be used to probe these mechanisms of disease and aid the design and development of new therapeutics against them.