Repurposing of Proton Pump Inhibitors as first identified small molecule inhibitors of endo-β-N-acetylglucosaminidase (ENGase) for the treatment of NGLY1 deficiency, a rare genetic disease

Bioorg Med Chem Lett. 2017 Jul 1;27(13):2962-2966. doi: 10.1016/j.bmcl.2017.05.010. Epub 2017 May 5.


N-Glycanase deficiency, or NGLY1 deficiency, is an extremely rare human genetic disease. N-Glycanase, encoded by the gene NGLY1, is an important enzyme involved in protein deglycosylation of misfolded proteins. Deglycosylation of misfolded proteins precedes the endoplasmic reticulum (ER)-associated degradation (ERAD) process. NGLY1 patients produce little or no N-glycanase (Ngly1), and the symptoms include global developmental delay, frequent seizures, complex hyperkinetic movement disorder, difficulty in swallowing/aspiration, liver dysfunction, and a lack of tears. Unfortunately, there has not been any therapeutic option available for this rare disease so far. Recently, a proposed molecular mechanism for NGLY1 deficiency suggested that endo-β-N-acetylglucosaminidase (ENGase) inhibitors may be promising therapeutics for NGLY1 patients. Herein, we performed structure-based virtual screening utilizing FDA-approved drug database on this ENGase target to enable repurposing of existing drugs. Several Proton Pump Inhibitors (PPIs), a series of substituted 1H-benzo [d] imidazole, and 1H-imidazo [4,5-b] pyridines, among other scaffolds, have been identified as potent ENGase inhibitors. An electrophoretic mobility shift assay was employed to assess the inhibition of ENGase activity by these PPIs. Our efforts led to the discovery of Rabeprazole Sodium as the most promising hit with an IC50 of 4.47±0.44μM. This is the first report that describes the discovery of small molecule ENGase inhibitors, which can potentially be used for the treatment of human NGLY1 deficiency.

Keywords: Drug repurposing; NGLY1; Proton Pump Inhibitors; Structure-based virtual screening; endo-β-N-Acetylglucosaminidase (ENGase) inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Genetic Diseases, Inborn / drug therapy*
  • Genetic Diseases, Inborn / genetics
  • Humans
  • Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase / antagonists & inhibitors
  • Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase / metabolism
  • Molecular Structure
  • Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase / deficiency
  • Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase / metabolism
  • Proton Pump Inhibitors / chemical synthesis
  • Proton Pump Inhibitors / chemistry
  • Proton Pump Inhibitors / pharmacology*
  • Proton Pumps / metabolism*
  • Rabeprazole / chemical synthesis
  • Rabeprazole / chemistry
  • Rabeprazole / pharmacology*
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship


  • Enzyme Inhibitors
  • Proton Pump Inhibitors
  • Proton Pumps
  • Small Molecule Libraries
  • Rabeprazole
  • Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase
  • Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase