Sialin, encoded by the SLC17A5 gene, is a lysosomal sialic acid transporter defective in Salla disease, a rare inherited leukodystrophy. It also enables metabolic incorporation of exogenous sialic acids, leading to autoantibodies against N-glycolylneuraminic acid in humans. Here, we identified a novel class of human sialin ligands by virtual screening and structure–activity relationship studies. The ligand scaffold is characterized by an amino acid backbone with a free carboxylate, an N-linked aromatic or heteroaromatic substituent, and a hydrophobic side chain. The most potent compound, 45 (LSP12-3129), inhibited N-acetylneuraminic acid 1 (Neu5Ac) transport in a non-competitive manner with IC₅₀ ≈ 2.5 μM, a value 400-fold lower than the K_M for Neu5Ac. In vitro and molecular docking studies attributed the non-competitive character to selective inhibitor binding to the Neu5Ac site in a cytosol-facing conformation. Moreover, compound 45 rescued the trafficking defect of the pathogenic mutant (R39C) causing Salla disease. This new class of cell-permeant inhibitors provides tools to investigate the physiological roles of sialin and help develop pharmacological chaperones for Salla disease.

中文翻译：

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带有芳香或杂芳族取代基的氨基酸，作为溶酶体唾液酸转运蛋白唾液酸的新型配体。

Sial17是SLC17A5基因编码的唾液酸唾液酸转运蛋白，在Salla病（一种罕见的遗传性白细胞营养不良）中有缺陷。它还可以使外源唾液酸代谢结合，从而导致人类抗N-羟乙酰神经氨酸的自身抗体。在这里，我们通过虚拟筛选和结构-活性关系研究确定了一类新型的人类唾液酸配体。配体支架的特征在于具有自由羧酸盐，N-连接的芳族或杂芳族取代基和疏水性侧链的氨基酸主链。最有效的化合物45（LSP12-3129）抑制N-乙酰神经氨酸1（Neu5Ac的）传输以非竞争的方式与IC ₅₀ ≈2.5μM，值大于400倍下ķ_中号为的Neu5Ac。体外和分子对接研究将这种非竞争性特征归因于选择性抑制剂与面向细胞溶胶的构象中的Neu5Ac位点结合。此外，化合物45挽救了引起Salla病的致病突变体（R39C）的运输缺陷。这类新型的细胞渗透抑制剂为研究唾液酸的生理作用提供了工具，并有助于开发针对Salla疾病的药理伴侣。