Bunyatov Mehman I, Boons Geert-Jan
Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, and Bijvoet Center for Biomolecular Research, Utrecht University, 3584 CG Utrecht, The Netherlands.
Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602, United States.
J Am Chem Soc. 2025 Jul 23;147(29):25306-25315. doi: 10.1021/jacs.5c04179. Epub 2025 Jul 8.
Several neuropathies, such as Guillain-Barré syndrome and myelin-associated glycoprotein neuropathy (MAG), are caused by antibodies targeting glycosphingolipids. Several studies have indicated that MAG arises from pathogenic IgM autoantibodies targeting sulfoglucuronyl (HNK-1)-containing glycosphingolipids. The exact mechanism by which IgM neuropathy occurs has not been fully elucidated. Furthermore, no appropriate diagnostic tools are available for MAG using sulfoglucuronyl-containing glycosphingolipids. To address these limitations, we describe here a synthetic strategy that makes it possible to prepare sulfoglucuronyl paraglobosides using a chemoenzymatic approach. It is based on the enzymatic assembly of -acetyllactosamine (LacNAc) backbones as thioglycosides that were subjected to protecting group manipulations to give glycosyl acceptors for the chemical installation of a sulfated glucuronic acid moiety. A late-stage conversion of the thioglycosides into anomeric fluorides made it possible to enzymatically introduce sphingosine. The resulting compounds were acylated to provide 3-sulfo-glucuronyl- and glucuronyl-containing glycosphingolipids, respectively. The glycosphingolipids were employed to remodel the surface of erythrocytes to examine complement-mediated toxicity by an anti-HNK-1 antibody. It was found that erythrocytes remodeled with exogenously administered HNK-1 containing glycosphingolipid undergo complement-dependent lysis when incubated with an anti-CD57 IgM antibody, whereas a compound lacking a sulfate was not able to induce this effect. The approach could be extended to the gangliosides GM1a and GD1a, which have been implicated in Guillain-Barré syndrome. The results highlight that cell surface remodeling will be attractive for diagnosis, disease monitoring, and immunological research of diseases associated with pathogenic antibodies targeting glycosphingolipids.
几种神经病变，如吉兰-巴雷综合征和髓鞘相关糖蛋白神经病变（MAG），是由靶向糖鞘脂的抗体引起的。多项研究表明，MAG源于靶向含磺基葡萄糖醛酸（HNK-1）的糖鞘脂的致病性IgM自身抗体。IgM神经病变发生的确切机制尚未完全阐明。此外，目前还没有使用含磺基葡萄糖醛酸的糖鞘脂对MAG进行诊断的合适工具。为了解决这些局限性，我们在此描述一种合成策略，该策略能够使用化学酶法制备磺基葡萄糖醛酸副球蛋白。它基于将β-乙酰乳糖胺（LacNAc）骨架作为硫代糖苷进行酶促组装，然后对其进行保护基操作，以得到用于化学安装硫酸化葡萄糖醛酸部分的糖基受体。硫代糖苷在后期转化为异头氟化物，从而能够酶促引入鞘氨醇。所得化合物分别进行酰化，以提供含3-磺基葡萄糖醛酸和葡萄糖醛酸的糖鞘脂。这些糖鞘脂被用于重塑红细胞表面，以检测抗HNK-1抗体介导的补体毒性。结果发现，用外源性给予的含HNK-1糖鞘脂重塑的红细胞在与抗CD57 IgM抗体孵育时会发生补体依赖性裂解，而缺乏硫酸盐的化合物则不能诱导这种效应。该方法可扩展至与吉兰-巴雷综合征有关的神经节苷脂GM1a和GD1a。这些结果表明，细胞表面重塑对于与靶向糖鞘脂的致病性抗体相关疾病的诊断、疾病监测和免疫学研究将具有吸引力。
