Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 63, Issue 15, Pages 8231-8249Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b02119
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Funding
- Agence Nationale de la Recherche [ANR-15-CE14-0001-02]
- Association Nationale de la Recherche et de la Technologie (ANRT)
- Dassault Systemes BIOVIA (CIFRE PhD scholarship) [2018/0027]
- Ministere de l'Enseignement Superieur, de la Recherche et de l'Innovation
- Neuropole Region Ile-de-France
- Science Ambassador Program from Dassault Systemes BIOVIA
- Agence Nationale de la Recherche (ANR) [ANR-15-CE14-0001] Funding Source: Agence Nationale de la Recherche (ANR)
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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 approximate to 2.5 mu M, 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.
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