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

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.