2. Academic Validation
  3. C-Branched Iminosugars as Selective Pharmacological Chaperones of Lysosomal α-Glucosidase for the Treatment of Pompe Disease

C-Branched Iminosugars as Selective Pharmacological Chaperones of Lysosomal α-Glucosidase for the Treatment of Pompe Disease

  • J Med Chem. 2025 Sep 25;68(18):19269-19286. doi: 10.1021/acs.jmedchem.5c01349.
Anaïs Vieira Da Cruz 1,  Valentine Perraudin 1,  Nadia Minopoli 2,  Roberta Iacono 3 4,  Véronique Roig-Zamboni 5,  Andrea Bossio 1,  Salia Tangara 1,  Martine Fayolle 1,  Alice Kanazawa 1,  Christian Philouze 1,  Antonietta Tarallo 2 6,  Jurriaan J A Heming 7,  Marta Artola 7,  Jean-Bernard Behr 8,  Herman S Overkleeft 7,  Marco Moracci 3 4,  Gerlind Sulzenbacher 5,  Giancarlo Parenti 2 6,  Sandrine Py 1
Affiliations

Affiliations

  • 1 Université Grenoble Alpes, CNRS, DCM, 38000 Grenoble, France.
  • 2 Telethon Institute of Genetics & Medicine, Via Campi Flegrei 34, I-80078 Pozzuoli, Italy.
  • 3 Department of Biology, University of Naples "Federico II", Complesso Universitario di Monte S. AngeloVia Cinthia 21, 80127 Naples, Italy.
  • 4 National Biodiversity Future Center (NBFC), 90133 Palermo, Italy.
  • 5 Architecture et Fonction des Macromolécules Biologiques (AFMB), CNRS, Aix-Marseille University, 13288 Marseille, France.
  • 6 Department of Translational Medical Sciences, Federico II University, Via S. Pansini 5, I-80131 Naples, Italy.
  • 7 Department of Medical Biochemistry and Department of Bioorganic Synthesis, Leiden Institute of Chemistry (LIC), Leiden University, Leiden 2333 CC, The Netherlands.
  • 8 Université de Reims Champagne-Ardenne, CNRS, ICMR, 51100 Reims, France.
PMID: 40951993 DOI: 10.1021/acs.jmedchem.5c01349
Abstract

We report herein the design and synthesis of a series of 5-C-alkyldeoxynojirimycins from l-sorbose, through an efficient and scalable method amenable to preparing a large variety of analogues. The interaction of this class of compounds with human acid α-glucosidase (GAA), the genetically defective enzyme in patients suffering from Pompe disease, was investigated to identify pharmacological chaperones exhibiting high selectivity for this enzyme. Crystallographic analyses provided a rationale for their binding mode to GAA and chaperone activity. The effects of 5-C-phenethyl-DNJ (4c) were evaluated on GAA activity enhancement in cells from Pompe disease patients and in vivo in GAA-KO mice. The significant increase of GAA activity in the presence of 4c in various tissues, particularly in the diaphragm, encourages further studies on this class of small molecules toward developing clinical drugs. Their chaperone activity and excellent selectivity may offer potential benefits over the current treatments for Pompe disease.

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