Glycopolymer immunomodulators by design: synthetic tools for exploiting the glycocode

背景：“甜蜜”疗法--为什么它们很重要？碳水化合物和蛋白质的相互作用调节了自然界中过多的关键事件，从受精到寄生化，再到免疫反应的增强。单糖(如葡萄糖和果糖)通常与其相应的蛋白质受体结合得太弱而不能在体内触发任何这些事件。大自然通过利用更大且往往极其复杂的碳水化合物与其相应的蛋白质受体具有更高和更具选择性的亲和力来克服这一问题。然而，尽管这些天然产生的蛋白质结合糖是非常有价值的潜在疗法，但通常不可能从天然来源中大规模分离和高纯度，而它们在合成实验室中的制备可能会受到极其昂贵和复杂的程序的阻碍。人工合成的糖共聚物--一类在其结构中显示多个“简单”糖拷贝的聚合物--刚刚开始作为复杂的天然蛋白质结合复合糖的极有价值的模拟物出现。新型糖聚合物-蛋白质杂化材料能提供什么？这些材料是本申请中描述的概念验证研究的最佳测试平台。PI之前设计了一种创新的、非常有效的路线来获得一系列新型的糖共聚物。他还设计了一种新型的杂化材料，由蛋白质和适当的糖基聚合物组成，具有双重性质：糖基聚合物可以将这些材料定向到血浆、细胞和组织中的特定治疗靶点，而蛋白质成分可以提供进一步的治疗活性，例如利用免疫系统治疗疾病。免疫反应源于极其复杂但精确协调的级联过程，人体利用这些过程来保护自己免受外来病原体的侵袭或避免肿瘤的发展。树突状细胞(DC)是免疫系统的哨兵，将病原体入侵或其他疾病发展的消息传递给其他免疫细胞，以触发适当的免疫反应。树突状细胞具有许多受体，其中很大一部分受体识别特定的复杂碳水化合物，并利用它们来触发其生物学功能。成本效益高和有效的疗法可以有效地激活DC以触发对癌细胞的免疫反应或控制自身免疫性疾病，这将对发展中国家和老龄化人口的医学和保健应用产生巨大影响。在这种背景下，聚合物-蛋白质杂化材料是一种具有巨大潜力的工具，可用于探索一系列生物途径，并最终有助于开发更安全、更具成本效益的治疗方法。激发对癌症或感染的保护性免疫，以及改善由免疫系统有害激活引起的疾病，是医疗保健和医学中最大的全球目标之一。缺乏价格合理的有效免疫调节剂是发展免疫疗法的主要障碍之一。这是这项应用的主要长期目标，这方面的进展可能会对学术界、工业界和社会产生广泛的影响。一个明显的商业应用将是一种与肿瘤标志物相结合的混合治疗方法，它可以指导我们的免疫系统识别并最终根除特定的癌症。更长期的发展可以通过开发包括癌症疫苗在内的免疫调节剂疗法产生影响。仅在欧盟，每年就有300多万人被诊断患有癌症--欧洲人口的老龄化将导致这些数字继续增加，即使特定年龄的比率保持不变--非常明显，癌症免疫疗法的重大发展将如何对我们的社会产生巨大的积极影响。

Context: 'Sweet' therapeutics - why are they important?Carbohydrate-protein interactions mediate a plethora of key events in Nature, spanning from fertilisation to parasitisation and the mounting of immune responses. Simple monosaccharides (e.g. glucose and fructose) often bind their corresponding protein receptors too weakly to trigger any these in vivo events. Nature overcomes this problem by utilising larger and often extremely complex carbohydrates with higher and more selective affinity to their corresponding protein receptors. However, while being extremely valuable potential therapeutics, these naturally occurring protein-binding sugars are often impossible to isolate on a large scale and high purity from natural sources, while their preparation in synthetic laboratories can be hampered by extremely expensive and complex procedures. Synthetic glycopolymers - a class of polymers which display multiple copies of "simpler" sugars in their structure - have just now started to emerge as extremely valuable mimics for complex naturally occurring protein-binding complex sugars. What do novel sugar polymer-protein hybrid materials have to offer?These materials are an optimal test platform for proof-of-concept studies described in this application. The PI has previously designed an innovative and extremely efficient route to a range of novel glycopolymers. He also has engineered novel a new class of hybrid materials composed by a protein and an appropriate glycopolymer with dual properties: the glycopolymer can direct these materials to specific therapeutic targets in plasma, cells, and tissues, while the protein component can provide further therapeutic activity, e.g. harnessing the immune system to treat diseases. Immune responses stem from extremely complex yet precisely coordinated cascades of processes which the human body utilises for as a protection against foreign pathogens or to avoid neoplastic development. Dendritic cells (DCs) are the sentinels of the immune system, and bring news of the invasion of pathogens or development of other diseases to other immune cells to trigger an appropriate immune response. DCs possess a number of receptors, a great proportion of which recognise specific complex carbohydrates and use them to trigger their biological functions. Cost-effective and efficacious therapeutics that could efficiently activate DC to trigger an immune response against cancer cells or to control autoimmune diseases would have a tremendous impact on medicine and healthcare applications both in developing nations and for ageing populations. Within this context polymer-protein hybrid materials are tools that hold great potential for probing of a range of biological pathways and ultimately contribute to develop safer and more cost-effective therapeutics.Impact.Elicitation of protective immunity against cancer or infection, and the amelioration of diseases caused by the harmful activation of the immune system are amongst the biggest global goals in healthcare and medicine. The lack of effective immunomodulators at an affordable price is one of the major obstacles to the development of immunotherapies. This is a major long term objective of this application and progress here could have widespread implications for academia, industry and the society alike. An obvious commercial application would be a hybrid therapeutic assembled with tumour markers which could instruct our immune system to recognise and ultimately eradicate specific cancers. Longer-term development could generate impact through the development of immunomodulator therapeutics including cancer vaccines. With over 3 million people diagnosed with cancer every year in the EU alone - and the ageing of the European population will cause these numbers to continue to increase even if age-specific rates remain constant - is very clear how significant development in cancer immunotherapy would have a dramatic positive impact our society.