Glycopolymer immunomodulators by design: synthetic tools for exploiting the glycocode

背景：“甜蜜”疗法——为什么重要？碳水化合物-蛋白质相互作用介导了自然界中大量的关键事件，从受精到寄生和免疫反应的增加。简单的单糖（如葡萄糖和果糖）往往结合其相应的蛋白质受体太弱，无法触发任何这些体内事件。大自然通过利用更大的、通常是极其复杂的碳水化合物来克服这个问题，这些碳水化合物对相应的蛋白质受体具有更高、更强的选择性亲和力。然而，虽然这些天然存在的蛋白质结合糖是极有价值的潜在治疗药物，但通常不可能从天然来源中大规模和高纯度地分离出来，而在合成实验室中制备它们可能受到极其昂贵和复杂程序的阻碍。合成的糖共聚物——一类在结构上具有多个“简单”糖副本的聚合物——刚刚开始成为复杂的天然蛋白质结合复合糖的极有价值的模仿物。新的糖-聚合物-蛋白质混合材料能提供什么？这些材料是本应用程序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、极其有效的途径来生产一系列新型的糖共聚物。他还设计了一种由蛋白质和具有双重特性的适当糖共聚物组成的新型混合材料：糖共聚物可以将这些材料导向血浆、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抵御外来病原体或避免肿瘤的发展。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生的消息传递给其他免疫细胞，以触发适当的免疫反应。dc拥有许多受体，其中很大一部分识别特定的复杂碳水化合物并利用它们触发其生物功能。能够有效地激活DC以触发针对癌细胞的免疫反应或控制自身免疫性疾病的具有成本效益和有效的治疗方法，将对发展中国家和老龄人口的医学和保健应用产生巨大影响。在这种情况下，聚合物-蛋白质混合材料是一种具有巨大潜力的工具，可以探索一系列生物途径，并最终有助于开发更安全、更经济的治疗方法。影响：激发对癌症或感染的保护性免疫，以及改善由免疫系统的有害激活引起的疾病，是医疗保健和医学领域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。这是这项应用的一个主要的长期目标，这里的进展可能对学术界、工业界和社会都有广泛的影响。一个明显的商业应用将是与肿瘤标志物组合的混合疗法，它可以指导我们的免疫系统识别并最终根除特定的癌症。长期发展可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，每年就有超过300万人被诊断患有癌症，而且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，癌症免疫疗法的重大发展将对我们的社会产生巨大的积极影响，这一点非常清楚。

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.