ArticleChembiochem : a European journal of chemical biology2008
Identification of pharmacological chaperones for Gaucher disease and characterization of their effects on beta-glucocerebrosidase by hydrogen/deuterium exchange mass spectrometry.
Article in Chembiochem : a European journal of chemical biology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 74 citations in OpenAlex.
- Computational evaluation of EPA-PC binding to GCase in neuronopathic Gaucher disease.Current research in structural biology · 2026Article
- High-throughput screening for small-molecule stabilizers of misfolded glucocerebrosidase in Gaucher disease and Parkinson's disease.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Review
- Development of quantitative high-throughput screening assays to identify, validate, and optimize small-molecule stabilizers of misfolded β-glucocerebrosidase with therapeutic potential for Gaucher disease and Parkinson's disease.bioRxiv : the preprint server for biology · 2024Article
- GBA1 Variants and Parkinson's Disease: Paving the Way for Targeted Therapy.Journal of movement disorders · 2023Article
- Second-Generation Pharmacological Chaperones: Beyond Inhibitors.Molecules (Basel, Switzerland) · 2020Review
- Simultaneous Control of Endogenous and User-Defined Genetic Pathways Using Unique ecDHFR Pharmacological Chaperones.Cell chemical biology · 2020Article
- Conversion of Quinazoline Modulators from Inhibitors to Activators of β-Glucocerebrosidase.Journal of medicinal chemistry · 2019Article
- β-Glucocerebrosidase Modulators Promote Dimerization of β-Glucocerebrosidase and Reveal an Allosteric Binding Site.Journal of the American Chemical Society · 2018Article
- Design and Synthesis of Potent Quinazolines as Selective β-Glucocerebrosidase Modulators.Journal of medicinal chemistry · 2016Article
- QUDeX-MS: hydrogen/deuterium exchange calculation for mass spectra with resolved isotopic fine structure.BMC bioinformatics · 2014Article
- Gaucher iPSC-derived macrophages produce elevated levels of inflammatory mediators and serve as a new platform for therapeutic development.Stem cells (Dayton, Ohio) · 2014Article
- Alteration of the proteostasis network of plant cells promotes the post-endoplasmic reticulum trafficking of recombinant mutant (L444P) human β-glucocerebrosidase.Plant signaling & behavior · 2014Article
- Insights into mucopolysaccharidosis I from the structure and action of α-L-iduronidase.Nature chemical biology · 2013Article
- Ambroxol as a pharmacological chaperone for mutant glucocerebrosidase.Blood cells, molecules & diseases · 2013Article
- Pharmacological chaperones facilitate the post-ER transport of recombinant N370S mutant β-glucocerebrosidase in plant cells: evidence that N370S is a folding mutant.Molecular genetics and metabolism · 2012Article
- Discovery, structure-activity relationship, and biological evaluation of noninhibitory small molecule chaperones of glucocerebrosidase.Journal of medicinal chemistry · 2012Article
- Positive lysosomal modulation as a unique strategy to treat age-related protein accumulation diseases.Rejuvenation research · 2012Article
- Production of active human glucocerebrosidase in seeds of Arabidopsis thaliana complex-glycan-deficient (cgl) plants.Glycobiology · 2012Article
- Advanced mass spectrometry-based methods for the analysis of conformational integrity of biopharmaceutical products.Current pharmaceutical biotechnology · 2011Review
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
Point mutations in beta-glucocerebrosidase (GCase) can result in a deficiency of both GCase activity and protein in lysosomes thereby causing Gaucher Disease (GD). Enzyme inhibitors such as isofagomine, acting as pharmacological chaperones (PCs), increase these levels by binding and stabilizing the native form of the enzyme in the endoplasmic reticulum (ER), and allow increased lysosomal transport of the enzyme. A high-throughput screen of the 50,000-compound Maybridge library identified two, non-carbohydrate-based inhibitory molecules, a 2,4-diamino-5-substituted quinazoline (IC(50) 5 microM) and a 5-substituted pyridinyl-2-furamide (IC(50) 8 microM). They raised the levels of functional GCase 1.5-2.5-fold in N370S or F213I GD fibroblasts. Immunofluorescence confirmed that treated GD fibroblasts had decreased levels of GCase in their ER and increased levels in lysosomes. Changes in protein dynamics, monitored by hydrogen/deuterium-exchange mass spectrometry, identified a domain III active-site loop (residues 243-249) as being significantly stabilized upon binding of isofagomine or either of these two new compounds; this suggests a common mechanism for PC enhancement of intracellular transport.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.