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

  • J Med Chem. 2020 Aug 13;63(15):8231-8249. doi: 10.1021/acs.jmedchem.9b02119.
Lilian Dubois  1 ,  Nicolas Pietrancosta  2  3 ,  Alexandre Cabaye  1  4 ,  Isabelle Fanget  5 ,  Cécile Debacker  5 ,  Pierre-André Gilormini  6 ,  Patrick M Dansette  1 ,  Julien Dairou  1 ,  Christophe Biot  6 ,  Roseline Froissart  7 ,  Anne Goupil-Lamy  4 ,  Hugues-Olivier Bertrand  4 ,  Francine C Acher  1 ,  Isabelle McCort-Tranchepain  1 ,  Bruno Gasnier  5 ,  Christine Anne  5
Affiliations
  • 1. Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS, UMR 8601, Université de Paris, F-75006 Paris, France.
  • 2. Laboratoire des Biomolécules, LBM, Sorbonne Université, École Normale Supérieure, PSL University, CNRS, F-75005 Paris, France.
  • 3. Neurosciences Paris Seine - Institut de Biologie Paris Seine (NPS - IBPS), Sorbonne Université, INSERM, CNRS, F-75005 Paris, France.
  • 4. BIOVIA, Dassault Systèmes, F-78140 Velizy-Villacoublay, France.
  • 5. SPPIN - Saints-Pères Paris Institute for the Neurosciences, CNRS, Université de Paris, F-75006 Paris, France.
  • 6. UMR 8576, UGSF, Unité de Glycobiologie et Fonctionnelle, Université de Lille, CNRS, F-59650 Lille, France.
  • 7. Service de Biochimie et Biologie Moléculaire Grand Est, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, F-69677 Bron, France.
PMID: 32608236 DOI: 10.1021/acs.jmedchem.9b02119
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.