Glycans attaching to Noroviruses - Allosteric Cross talk meets post translational modification

最近，我们使用了所谓的基于配体的核磁共振技术，如STD核磁共振技术来研究碳水化合物与兔出血症病毒(RHDV)和人类诺如病毒的结合。我们成功地合成了有效的第一代进入抑制物来对抗人诺如病毒感染。一个主要的缺点是缺乏细胞培养系统或动物模型来进一步测试这些原型抑制剂的疗效。我们实验室最新的核磁共振研究表明，人类诺如病毒与组织血型抗原的结合比预期的要复杂得多。我们认为，这适用于所有杯状病毒-葡聚糖相互作用，并对病毒进入有影响。因此，我们将应用我们的核磁共振方法来研究碳水化合物与小鼠诺如病毒的结合，作为一个模型系统，其中有细胞培养系统和动物模型(Taube实验室)。此外，我们还将鉴定与小鼠诺如病毒结合的分子片段，并与哈特曼实验室合作，设计和合成抑制病毒进入的多价配体。这些新的配体将作为研究病毒进入体内的分子细节的工具，从而揭示感染过程中鲜为人知的方面。这项工作有可能为抗病毒疗法的发展发现新的策略。

Lately, we have used so-called ligand based NMR-techniques such as STD NMR to study carbohydrate binding to rabbit hemorrhagic disease virus (RHDV) and human noroviruses. We succeeded in synthesizing potent first generation entry inhibitors against human norovirus infection. A major drawback was the lack of cell culture systems, or animal models to further test the efficacy of these prototype inhibitors. Latest NMR studies in our laboratory suggest that binding of human noroviruses to histo-blood group antigens is much more complex than anticipated. We propose that this holds for all calicivirus-glycan interactions and has implications for virus entry. Therefore, we will apply our NMR methodology to study carbohydrate binding to murine noroviruses as a model system where cell culture systems and an animal model are available (Taube laboratory). Along with this we will identify molecular fragments that bind to murine noroviruses, and in collaboration with the Hartmann laboratory we will design and synthesize multivalent ligands for entry inhibition. These novel ligands will serve as tools to study molecular details of virus entry in vivo, and thus shine light on poorly understood aspects of the infection process. This work has the potential to uncover new strategies for the development of antiviral therapies.