Morquio A syndrome is a lysosomal disorder caused by the deficiency of the lysosomal enzyme N-acetylgalactosamine 6-sulfatase (GALNS, EC 3.1.6.4). Currently, enzyme replacement therapy (ERT) is used to treat Morquio A through the infusion of the recombinant enzyme VIMIZIM^® (elosulfase alfa, BioMarin). Unfortunately, the recombinant enzyme exhibits low conformational stability in vivo. A promising approach to address this issue is the coadministration of recombinant human GALNS (rhGALNS) with a pharmacological chaperone (PC), a molecule that selectively binds to the misfolded protein, stabilizes its conformation, and assists in the restoration of the impaired function. We report in this work the synthesis of a library of multivalent glycomimetics exploiting the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction between several dendrimeric scaffolds armed with terminal alkynes and azido ending iminosugars of different structures (pyrrolidines, piperidines, and pyrrolizidines) or simple azido ending carbohydrates as bioactive units. The biological evaluation identified pyrrolidine-based nonavalent dendrimers 1 and 36 as the most promising compounds, able both to bind the native enzyme with IC₅₀ in the micromolar range and to act as enzyme stabilizers toward rhGALNS in a thermal denaturation study, thus identifying promising compounds for a combined PC/ERT therapy.

Keywords: Morquio A; N-acetylgalactosamine 6-sulfatase; dendrimers; enzyme stabilizers; iminosugars; multivalent glycomimetics.

莫奎奥A综合征是一种溶酶体疾病，由溶酶体酶N-乙酰半乳糖胺6-硫酸酯酶（GALNS，EC 3.1.6.4）缺乏引起。目前通过静脉输注重组酶VIMIZIM^® (elosulfase alfa, BioMarin) 进行溶酶体酶替代疗法（ERT）来治疗莫奎奥A综合征。不幸的是，重组酶在体内表现出较低的构象稳定性。解决这一问题的一个有前景的方法是联合给药重组人GALNS (rhGALNS) 和一种药物伴侣 (PC)，即选择性结合错误折叠蛋白质、稳定其构象并帮助恢复受损功能的分子。在这项工作中，我们报告了通过铜(I)-催化的叠氮-炔环加成（CuAAC）反应合成一系列多价糖模拟物的过程，该反应将多个带有末端炔基的树状支架与不同结构（吡咯烷、哌啶和吡咯嗪）的末端叠氮基胺糖或简单的末端叠氮基碳水化合物生物活性单元连接起来。生物学评价确定了基于吡咯烷的非价树状分子1 和36 是最有前景的化合物，它们既能与天然酶结合（IC₅₀ 在微摩尔范围内），又能作为rhGALNS 的酶稳定剂在热变性研究中起作用，从而确定了用于联合PC/ERT疗法的有前景的化合物。

关键词：莫奎奥A；N-乙酰半乳糖胺6-硫酸酯酶；树状分子；酶稳定剂；胺糖；多价糖模拟物。