Design of ligand-based targeted delivery vehicles for the murine C-type lectin receptor Langerin

C型凝集素受体（CLRs）代表哺乳动物碳水化合物结合蛋白的最大和最多样化的家族。特别是，在专职抗原呈递细胞上表达为免疫细胞受体的CLR在健康和疾病中发挥重要功能，使其成为有吸引力的药物靶标。这样的CLR的小分子调节剂用作潜在的免疫刺激剂（即佐剂），或者可以用作连接至纳米颗粒的靶向部分，用于在例如癌症免疫疗法中主动递送免疫调节货物。然而，可重复用药性被认为相当低，这表明未来药物发现活动失败的风险增加。总的来说，这种假设导致缺乏药物样的抗肿瘤效应物，这一方面可以用于探索抗肿瘤免疫生物学的重要基础，以及具有很高的潜力被转化为临床应用。为此，我们已经确定了几个系列的小鼠受体Langerin的小分子配体。在小鼠中，这种基因在皮肤的特定树突细胞（所谓的朗格汉斯细胞）以及血液的树突细胞上表达。两种树突状细胞亚群都是基于小分子的免疫调节的有吸引力的靶点。先前发现的Langerin配体将经历片段生长方法以增加亲和力和特异性，从而最终用作附着于纳米颗粒的靶向配体。基本的洞察力将产生如何基于配体的免疫调节剂的靶向递送是由靶向配体的生物化学性质的影响，如受体结合位点的位置，其亲和力和动力学，我们假设这会导致改变摄取以及路由，释放和货物的处理。基于生物物理学、生物化学和细胞生物学表征的这些靶向配体的结构活性景观的密切检查是该提议的主要目标，并且不仅将打开CLRs领域以开发免疫调节方法，而且同时提供对基于配体的靶向递送的基本见解。

C-type lectin receptors (CLRs) represent the largest and most diverse family of mammalian carbohydrate-binding proteins. In particular, CLRs that are expressed as immune cell receptors on professional antigen presenting cells fulfill important functions in health and disease rendering them attractive drug targets. Such small molecule modulators of CLRs function as potential immune stimulants (i.e. adjuvants) or can be utilized as targeting moieties attached to nanoparticles for the active delivery of immunomodulatory cargo in e.g. cancer immunotherapy. However, CLR druggability is considered rather low, suggesting an increased risk of failure of future drug discovery campaigns. Overall, this presumption leads to a shortage of drug-like CLR effectors, which could on the one hand be used to explore important fundamentals in CLR immunobiology as well as having a high potential of being translated into clinical applications. To this end, we have identified several series of small molecule ligands for the murine receptor Langerin. This CLR is expressed in mice on specific dendritic cells of the skin, so-called Langerhans cells, as well as on dendritic cells of the blood. Both dendritic cell subsets are attractive targets for small molecule-based immunomodulation. The Langerin ligands previously discovered will be subject to fragment growing approaches to increase affinity and specificity to finally serve as targeting ligands attached to nanoparticles. Fundamental insight will be generated how ligand-based targeted delivery of immunomodulators is influenced by the biochemical properties of the targeting ligand such as location of the receptor binding site, their affinity and kinetics, which we hypothesize to result in an altered uptake as well as routing, release, and processing of the cargo. A close inspection of the structure activity landscape of these targeting ligands based on biophysical, biochemical and cell-biological characterization is the prime goal of this proposal and will not only open the field of CLRs to the development of immunomodulatory approaches, but at the same time provide fundamental insights into ligand-based targeted delivery.