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

C型凝集素受体(CLRs)是哺乳动物碳水化合物结合蛋白中最大、最多样的家族。特别是，在专业抗原提呈细胞上表达为免疫细胞受体的CLR在健康和疾病中发挥着重要的功能，使它们成为有吸引力的药物靶点。这种CLRs的小分子调节剂具有潜在的免疫刺激剂(即佐剂)的功能，或可用作附着在纳米颗粒上的靶向部分，用于主动传递免疫调节货物，例如在癌症免疫治疗中。然而，CLR的可药性被认为相当低，这表明未来药物发现活动失败的风险增加。总体而言，这一假设导致了类药物CLR效应器的短缺，一方面可以用来探索CLR免疫生物学的重要基础，同时也有很高的潜力转化为临床应用。为此，我们已经确定了小鼠受体Langerin的几个系列小分子配体。这种CLR在小鼠皮肤的特定树突状细胞上表达，即所谓的朗格汉斯细胞，以及血液中的树突状细胞。这两个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。以前发现的朗格林配体将受到片段生长方法的影响，以增加亲和力和特异性，最终作为连接到纳米颗粒上的靶向配体。基于配体的免疫调节剂的靶向递送如何受到靶向配体的生化特性的影响，如受体结合部位的位置、它们的亲和力和动力学，我们假设这些特性会导致货物的摄取以及路线、释放和加工的改变，从而产生基本的见解。根据生物物理、生化和细胞生物学特性对这些靶向配体的结构和活性图景进行密切检查是这一提议的主要目标，这不仅将为免疫调节方法的发展开辟CLR领域，同时也为基于配体的靶向递送提供基本的见解。

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.