Benjamin Stefi V, Taylor Maureen E, Drickamer Kurt
Department of Life Sciences, Sir Ernst Chain Building, Imperial College, London SW7 2AZ, United Kingdom.
Glycobiology. 2025 Feb 28;35(4). doi: 10.1093/glycob/cwaf011.
An increasing number of clinical applications employ oligosaccharides as tags to direct therapeutic proteins and RNA molecules to specific target cells. Current applications are focused on endocytic receptors that result in cellular uptake, but additional applications of sugar-based targeting in signaling and protein degradation are emerging. These approaches all require development of ligands that bind selectively to specific sugar-binding receptors, known as lectins. In the work reported here, a human lectin array has been employed as a predictor of targeting selectivity of different oligosaccharide ligands and as a rapid in vitro screen to identify candidate targeting ligands. The approach has been validated with existing targeting ligands, such as a synthetic glycomimetic GalNAc cluster ligand that targets siRNA molecules to hepatocytes through the asialoglycoprotein receptor. Additional small oligosaccharides that could selectively target other classes of cells have also been identified and the potential of larger glycans derived from glycoproteins has been investigated. In initial screens, potential ligands for targeting either vascular or sinusoidal endothelial cells and plasmacytoid dendritic cells have been identified. Lectin array screening has also been used to characterize the selectivity of glycolipid-containing liposomes that are used as carriers for targeted delivery. The availability of a rapid in vitro screening approach to characterizing natural oligosaccharides and glycomimetic compounds has the potential to facilitate selection of appropriate targeting tags before undertaking more complex in vivo studies such as measuring clearance in animals.
越来越多的临床应用采用寡糖作为标签，将治疗性蛋白质和RNA分子导向特定的靶细胞。目前的应用主要集中在内吞受体上，通过内吞作用实现细胞摄取，但基于糖的靶向在信号传导和蛋白质降解方面的其他应用也正在兴起。这些方法都需要开发能选择性结合特定糖结合受体（即凝集素）的配体。在本文报道的研究中，一种人凝集素阵列被用作不同寡糖配体靶向选择性的预测工具，以及用于鉴定候选靶向配体的快速体外筛选方法。该方法已通过现有的靶向配体得到验证，例如一种合成的糖模拟物GalNAc簇配体，它通过去唾液酸糖蛋白受体将siRNA分子靶向肝细胞。还鉴定出了其他能够选择性靶向其他细胞类型的小寡糖，并研究了源自糖蛋白的更大聚糖的潜力。在初步筛选中，已鉴定出靶向血管或窦状内皮细胞以及浆细胞样树突状细胞的潜在配体。凝集素阵列筛选还被用于表征用作靶向递送载体的含糖脂脂质体的选择性。一种用于表征天然寡糖和糖模拟化合物的快速体外筛选方法的出现，有可能在进行更复杂的体内研究（如测量动物体内清除率）之前，促进合适靶向标签的选择。
