title: Discovery of a novel noniminosugar acid α glucosidase chaperone series.
abstract: Pompe disease is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the lysosomal enzyme acid α-glucosidase (GAA). Many disease-causing mutated GAA retain enzymatic activity but are not translocated from endoplasmic reticulum (ER) to lysosomes. Enzyme replacement therapy (ERT) is the only treatment for Pompe disease but remains expensive, inconvenient, and does not reverse all disease manifestations. It was postulated that small molecules which aid in protein folding and translocation to lysosomes could provide an alternate to ERT. Previously, several iminosugars have been proposed as small-molecule chaperones for specific LSDs. Here we identified a novel series of noniminosugar chaperones for GAA. These moderate GAA inhibitors are shown to bind and thermostabilize GAA and increase GAA translocation to lysosomes in both wild-type and Pompe fibroblasts. AMDE and physical properties studies indicate that this series is a promising lead for further pharmacokinetic evaluation and testing in Pompe disease models.
authors: NIH Chemical Genomics Center, NIH Center for Translational Therapeutics, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, USA.
authors: Jingbo
authors: J
authors: Xiao
authors: Wendy
authors: W
authors: Westbroek
authors: Omid
authors: O
authors: Motabar
authors: Wendy A
authors: WA
authors: Lea
authors: Xin
authors: X
authors: Hu
authors: Arash
authors: A
authors: Velayati
authors: Wei
authors: W
authors: Zheng
authors: Noel
authors: N
authors: Southall
authors: Ann Marie
authors: AM
authors: Gustafson
authors: Ehud
authors: E
authors: Goldin
authors: Ellen
authors: E
authors: Sidransky
authors: Ke
authors: K
authors: Liu
authors: Anton
authors: A
authors: Simeonov
authors: Rafael J
authors: RJ
authors: Tamargo
authors: Antonia
authors: A
authors: Ribes
authors: Leslie
authors: L
authors: Matalonga
authors: Marc
authors: M
authors: Ferrer
authors: Juan J
authors: JJ
authors: Marugan
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D055808:Drug Discovery; D056947:Enzyme Replacement Therapy; D006009:Glycogen Storage Disease Type II / Q000188:drug therapy; D006801:Humans; D050111:Imino Sugars / Q000737:chemistry*; D007150:Immunohistochemistry; D009682:Magnetic Resonance Spectroscopy; D018613:Microscopy, Confocal; D018832:Molecular Chaperones; D054852:Small Molecule Libraries; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D000520:alpha-Glucosidases / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D050111:Imino Sugars; D018832:Molecular Chaperones; D054852:Small Molecule Libraries; D000520:alpha-Glucosidases