Discovery, structure-activity relationship, and biological evaluation of noninhibitory small molecule chaperones of glucocerebrosidase.

Paradigms and Technologies
Methods Development
Therapeutic Approaches
Medicinal Chemistry


A major challenge in the field of Gaucher disease has been the development of new therapeutic strategies including molecular chaperones. All previously described chaperones of glucocerebrosidase are enzyme inhibitors, which complicates their clinical development because their chaperone activity must be balanced against the functional inhibition of the enzyme. Using a novel high throughput screening methodology, we identified a chemical series that does not inhibit the enzyme but can still facilitate its translocation to the lysosome as measured by immunostaining of glucocerebrosidase in patient fibroblasts. These compounds provide the basis for the development of a novel approach toward small molecule treatment for patients with Gaucher disease.


Patnaik, Samarjit; Zheng, Wei; Choi, Jae H; Motabar, Omid; Southall, Noel; Westbroek, Wendy; Lea, Wendy A; Velayati, Arash; Goldin, Ehud; Sidransky, Ellen; Leister, William; Marugan, Juan;


  • Animals
  • Caco-2 Cells
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • Gaucher Disease/ drug therapy
  • Gaucher Disease/ enzymology
  • Glucosylceramidase/ metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Permeability
  • Pyrimidines/ chemistry
  • Pyrimidines/ metabolism
  • Pyrimidines/ pharmacokinetics
  • Pyrimidines/ pharmacology
  • Small Molecule Libraries/ chemistry
  • Small Molecule Libraries/ metabolism
  • Small Molecule Libraries/ pharmacokinetics
  • Small Molecule Libraries/ pharmacology
  • Structure-Activity Relationship

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