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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Immunoprotective neo-glycoproteins: Chemoenzymatic synthesis of multivalent glycomimetics for inhibition of cancer-related galectin-3
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Immunoprotective neo-glycoproteins: Chemoenzymatic synthesis of multivalent glycomimetics for inhibition of cancer-related galectin-3

机译：免疫保护新糖蛋白：化学酶合成多价甘草质，用于抑制癌症相关的Galectin-3

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Galectin-3 plays a crucial role in cancerogenesis; its targeting is a prospective pathway in cancer diagnostics and therapy. Multivalent presentation of glycans was shown to strongly increase the affinity of glycoconjugates to galectin-3. Further strengthening of interaction with galectin-3 may be accomplished using artificial glycomimetics with apt aryl substitutions. We established a new, as yet undescribed chemoenzymatic method to produce selective C-3-substituted N,N'-diacetyllactosamine glycomimetics and coupled them to human serum albumin. From a library of enzymes, only beta-N-acetylhexosaminidase from Talaromyces flavus was able to efficiently synthesize the C-3-propargylated disaccharide. Various aryl residues were attached to the functionalized N,N'-diacetyllactosamine via click chemistry to assess the impact of the aromatic substitution. In ELISA-type assays with galectin-3, free glycomimetics exhibited up to 43-fold stronger inhibitory potency to Gal-3 than the lactose standard. Coupling to human serum albumin afforded multivalent neo-glycoproteins with up to 4209-fold increased inhibitory potency per glycan compared to the monovalent lactose standard. Surface plasmon resonance brought further information on the kinetics of galectin-3 inhibition. The potential of prepared neo-glycoproteins to target galectin-3 was demonstrated on colorectal adenocarcinoma DLD-1 cells. We investigated the uptake of neo-glycoproteins into cells and observed limited non-specific transport into the cytoplasm. Therefore, neo-glycoproteins primarily act as efficient scavengers of exogenous galectin-3 of cancer cells, inhibiting its interaction with the cell surface, and protecting T-lymphocytes against galectin-3-induced apoptosis. The present neo-glycoproteins combine the advantage of a straightforward synthesis, selectivity, non-toxicity, and high efficiency for targeting exogenous galectin-3, with possible application in the immunomodulatory treatment of galectin-3-overexpressing cancers. (C) 2021 Elsevier Masson SAS. All rights reserved.
机译：半乳糖凝集素-3在癌症发生中起关键作用；它的靶向性是癌症诊断和治疗的一个有前景的途径。多糖的多价呈现被证明能显著增加糖缀合物与半乳糖凝集素-3的亲和力。进一步加强与半乳糖凝集素-3的相互作用可以通过使用具有apt芳基取代的人工拟糖体来实现。我们建立了一种新的、尚未描述的化学酶法来生产选择性C-3-取代的N，N'-二乙酰丙酮胺拟糖体，并将其与人血清白蛋白偶联。从一个酶库中，只有黄塔拉菌的β-N-乙酰己糖胺酶能够有效地合成C-3-丙炔基二糖。通过点击化学将各种芳基残基连接到功能化的N，N'-二乙酰丙酮胺上，以评估芳香取代的影响。在用半乳糖凝集素-3进行的ELISA型检测中，游离拟糖体对半乳糖-3的抑制效力是乳糖标准品的43倍。与人血清白蛋白偶联后，与单价乳糖标准相比，多价新糖蛋白的每个聚糖的抑制效力增加了4209倍。表面等离子体共振为半乳糖凝集素-3抑制的动力学提供了进一步的信息。在大肠腺癌DLD-1细胞上证明了制备的新糖蛋白靶向galectin-3的潜力。我们研究了新糖蛋白在细胞中的摄取，并观察到有限的非特异性转运到细胞质中。因此，新糖蛋白主要作为癌细胞外源性半乳糖凝集素-3的有效清除剂，抑制其与细胞表面的相互作用，保护T淋巴细胞免受半乳糖凝集素-3诱导的凋亡。目前的新糖蛋白结合了直接合成、选择性、无毒性和高效性的优点，用于靶向外源性半乳糖凝集素-3，并可能应用于半乳糖凝集素-3过度表达癌症的免疫调节治疗。（c）2021爱思唯尔马松SAS。版权所有。

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