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

ABSTRACT: 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-?-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±0.44?M. 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.

SUBMITTER: Bi Y

PROVIDER: S-EPMC5548696 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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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.

Bi Yiling Y Might Matthew M Vankayalapati Hariprasad H Kuberan Balagurunathan B

Bioorganic & medicinal chemistry letters 20170505 13

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, dif ...[more]

PMID: 28512024

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Project description:To evaluate the characteristics of the prescription of the proton pump inhibitor drugs (PPI) and the adherence to the indications of the guidelines regulating the reimbursement limitations set forth by the Italian Drug Agency.Thirty general practitioners (GP) participated in the study, providing data on more than 40000 patients in total. The population was divided into non occasional users of PPI drugs (PPI users) and non-users (PPI non-users) based on evidence of a prescription of at least 3 packs of PPIs in the last 90 d before analysis. The data provided allowed an assessment of compliance with the requirements of eligibility for PPI reimbursement according to the Italian Drug Agency rules, in order to obtain subpopulations which complied or not with the rules.Six thousand three hundred and twenty-two patients were found to be PPI users, accounting for 14.9% of the patient population. PPI users were more frequently female, older and more frequently diagnosed with gastroesophageal reflux disease, gastric or duodenal ulcers, arthropathy, heart disease and cancer than the rest of the population. PPI users had more frequently received prescriptions for non-steroidal ant-inflammatory drugs (NSAIDS), acetylsalicylic acid (ASA), oral anticoagulant therapy (OAT) and systemic steroids. PPI reimbursement resulted applicable to 69.3% of the PPI users, but a potential for reimbursement of PPI prescriptions was identified in the non PPI users for the treatment of peptic or reflux disease (8.5%) and for the protection of gastric damage caused by NSAIDS (6.1%). Patients who are potentially eligible for reimbursement are older, diagnosed with arthropathy and heart disease more frequently and most commonly receive NSAID and ASA prescriptions compared with PPI users who do not satisfy eligibility requirements. Patients in whom it was not possible to identify conditions related to prescription suitability were more frequently associated with use of OAT.A substantial number of patients who apparently do not meet prescription suitability conditions can be identified, but among non PPI users on the contrary, it is possible to identify an equal number of patients for whom prescription would be suitable. Poor suitability can be identified in the population receiving OAT. Thus, there is scope for decreasing inappropriate use of PPI drugs by adhering to certain criteria and by involving all interested parties.

Dataset Information

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

Publications

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.

Similar Datasets

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