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

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

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.

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