Amino Acids Bearing Aromatic or Heteroaromatic ...
Type de document :
Article dans une revue scientifique
URL permanente :
Titre :
Amino Acids Bearing Aromatic or Heteroaromatic Substituents as a New Class of Ligands for the Lysosomal Sialic Acid Transporter Sialin
Auteur(s) :
Dubois, Lilian [Auteur]
Pietrancosta, Nicolas [Auteur]
Cabaye, Alexandre [Auteur]
Fanget, Isabelle [Auteur]
Debacker, Cécile [Auteur]
Gilormini, Pierre-André [Auteur]
Dansette, Patrick M. [Auteur]
Dairou, Julien [Auteur]
Biot, Christophe [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Froissart, Roseline [Auteur]
Goupil-Lamy, Anne [Auteur]
Bertrand, Hugues-Olivier [Auteur]
Acher, Francine C. [Auteur]
McCort-Tranchepain, Isabelle [Auteur]
Gasnier, Bruno [Auteur]
Anne, Christine [Auteur]
Pietrancosta, Nicolas [Auteur]
Cabaye, Alexandre [Auteur]
Fanget, Isabelle [Auteur]
Debacker, Cécile [Auteur]
Gilormini, Pierre-André [Auteur]
Dansette, Patrick M. [Auteur]
Dairou, Julien [Auteur]
Biot, Christophe [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Froissart, Roseline [Auteur]
Goupil-Lamy, Anne [Auteur]
Bertrand, Hugues-Olivier [Auteur]
Acher, Francine C. [Auteur]
McCort-Tranchepain, Isabelle [Auteur]
Gasnier, Bruno [Auteur]
Anne, Christine [Auteur]
Titre de la revue :
Journal of Medicinal Chemistry
Nom court de la revue :
J. Med. Chem.
Numéro :
63
Pagination :
8231-8249
Éditeur :
American Chemical Society (ACS)
Date de publication :
2020-07-01
Mot(s)-clé(s) en anglais :
Peptides and proteins
Monomers
Inhibitors
Inhibition
Aromatic compounds
Monomers
Inhibitors
Inhibition
Aromatic compounds
Discipline(s) HAL :
Sciences du Vivant [q-bio]
Chimie/Chimie théorique et/ou physique
Chimie/Chimie théorique et/ou physique
Résumé en anglais : [en]
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 ...
Lire la suite >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.Lire moins >
Lire la suite >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.Lire moins >
Langue :
Anglais
Audience :
Internationale
Vulgarisation :
Non
Établissement(s) :
Université de Lille
CNRS
CNRS
Équipe(s) de recherche :
Chemical Glycobiology
Date de dépôt :
2021-01-28T13:20:26Z
2021-02-08T17:09:50Z
2021-02-08T17:09:50Z
Fichiers
- P20.29 Amino Acids Bearing.pdf
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