Amino Acids Bearing Aromatic or Heteroaromatic Substituents as a New Class of Ligands for the Lysosomal Sialic Acid Transporter Sialin.

Abstract

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 KM 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.

• Authors: Lilian Dubois, Nicolas Pietrancosta, Alexandre Cabaye, Isabelle Fanget, Cécile Debacker, Pierre-André Gilormini, Patrick M Dansette, Julien Dairou, Christophe Biot, Roseline Froissart, Anne Goupil-Lamy, Hugues-Olivier Bertrand, Francine C Acher, Isabelle McCort-Tranchepain, Bruno Gasnier, Christine Anne
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 63 Issue 15 Pg. 8231-8249 (08 13 2020) ISSN: 1520-4804 [Electronic] United States
• PMID: 32608236 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acids
• Ligands
• Organic Anion Transporters
• Symporters
• sialic acid transport proteins

Topics

• Amino Acids (chemistry, metabolism)
• Animals
• Dose-Response Relationship, Drug
• HEK293 Cells
• HeLa Cells
• Humans
• Ligands
• Lysosomes (metabolism)
• Molecular Docking Simulation (methods)
• Organic Anion Transporters (metabolism)
• Protein Structure, Secondary
• Rats
• Symporters (metabolism)