Galectin inhibitors are urgently needed to understand the mode of action and druggability of different galectins, but potent and selective agents still evade researchers. Small-sized inhibitors based on thiodigalactoside (TDG) have shown their potential while modifications at their C3 position indicated a strategy to improve selectivity and potency. Considering the role of galectins as glycoprotein traffic police, involved in multivalent bridging interactions, we aimed to create multivalent versions of the potent TDG inhibitors. We herein present for the first time the multivalent attachment of a TDG derivative using bovine serum albumin (BSA) as the scaffold. An efficient synthetic method is presented to obtain a novel type of neoglycosylated proteins loaded with different numbers of TDG moieties. A polyethylene glycol (PEG)-spacer is introduced between the TDG and the protein scaffold maintaining appropriate accessibility for an adequate galectin interaction. The novel conjugates were evaluated in galectin binding and inhibition studies in vitro. The conjugate with a moderate density of 19 conjugated TDGs was identified as one of the most potent multivalent Gal-3 inhibitors so far, with a clear demonstration of the benefit of a multivalent ligand presentation. The described method may facilitate the development of specific galectin inhibitors and their application in biomedical research.

中文翻译：

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硫代十二烷糖苷-牛血清白蛋白结合作为Galectin-3的高效抑制剂：小分子抑制剂的多价呈递实例。

迫切需要半乳糖凝集素抑制剂来了解不同半乳糖凝集素的作用方式和可塑性，但是有效的和选择性的药物仍在躲避研究人员。基于巯基二乙二糖苷（TDG）的小型抑制剂已显示出其潜力，而其C3位置的修饰则表明了一种提高选择性和效能的策略。考虑到半乳糖凝集素作为糖蛋白交通警察的作用，参与多价桥联相互作用，我们旨在创建有效的TDG抑制剂的多价形式。我们在此首次提出使用牛血清白蛋白（BSA）作为支架的TDG衍生物的多价连接。提出了一种有效的合成方法来获得一种新型的新糖基化蛋白，其中载有不同数量的TDG部分。在TDG和蛋白质支架之间引入了聚乙二醇（PEG）间隔子，以保持适当的可及性，以实现充分的半乳糖凝集素相互作用。在体外半乳凝素结合和抑制研究中评估了新型缀合物。具有中等密度的19个结合的TDG的结合物被认为是迄今为止最有效的多价Gal-3抑制剂之一，清楚地证明了多价配体的优势。所描述的方法可以促进特定半乳糖凝集素抑制剂的开发及其在生物医学研究中的应用。具有中等密度的19个结合的TDG的结合物被确定为迄今为止最有效的多价Gal-3抑制剂之一，清楚地证明了多价配体呈递的益处。所描述的方法可以促进特定半乳糖凝集素抑制剂的开发及其在生物医学研究中的应用。具有中等密度的19个结合的TDG的结合物被认为是迄今为止最有效的多价Gal-3抑制剂之一，清楚地证明了多价配体的优势。所描述的方法可以促进特定半乳糖凝集素抑制剂的开发及其在生物医学研究中的应用。