Discovery of a novel noniminosugar acid α glucosidase chaperone series

Jingbo Xiao, Wendy Westbroek, Omid Motabar, Wendy A. Lea, Xin Hu, Arash Velayati, Wei Zheng, Noel Southall, Ann Marie Gustafson, Ehud Goldin, Ellen Sidransky, Ke Liu, Anton Simeonov, Rafael J. Tamargo, Antonia Ribes, Leslie Matalonga, Marc Ferrer, Juan J. Marugan

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)7546-7559
Number of pages14
JournalJournal of medicinal chemistry
Volume55
Issue number17
DOIs
StatePublished - Sep 13 2012
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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