ArticleJournal of medicinal chemistry2007
Isofagomine- and 2,5-anhydro-2,5-imino-D-glucitol-based glucocerebrosidase pharmacological chaperones for Gaucher disease intervention.
Article in Journal of medicinal chemistry, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 141 citations in OpenAlex.
- Recent advances in adamantane-linked heterocycles: synthesis and biological activity.Molecular diversity · 2026Review
- The Race to Salvage Glucocerebrosidase: Understanding Small-Molecule Therapies for GBA1-Associated Parkinsonism.Movement disorders : official journal of the Movement Disorder Society · 2026Review
- 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
- A practical synthesis of nitrone-derived C5a-functionalized isofagomines as protein stabilizers to treat Gaucher disease.Communications chemistry · 2024Article
- 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
- Mechanistic Insight into the Mode of Action of Acid β-Glucosidase Enhancer Ambroxol.International journal of molecular sciences · 2022Article
- Pharmacologic Approaches for Adapting Proteostasis in the Secretory Pathway to Ameliorate Protein Conformational Diseases.Cold Spring Harbor perspectives in biology · 2020Review
- Selective Targeting of the Interconversion between Glucosylceramide and Ceramide by Scaffold Tailoring of Iminosugar Inhibitors.Molecules (Basel, Switzerland) · 2019Article
- Expanding role of molecular chaperones in regulating α-synuclein misfolding; implications in Parkinson's disease.Cellular and molecular life sciences : CMLS · 2017Review
- Catalyst-free multicomponent synthesis of novel adamantyl-containing tetrahydropyrimidine carboxylates.Molecular diversity · 2016Article
- Pharmacological Chaperone Therapy: Preclinical Development, Clinical Translation, and Prospects for the Treatment of Lysosomal Storage Disorders.Molecular therapy : the journal of the American Society of Gene Therapy · 2015Review
- Using pharmacological chaperones to restore proteostasis.Pharmacological research · 2014Review
- The lipophilic bullet hits the targets: medicinal chemistry of adamantane derivatives.Chemical reviews · 2013Review
- Ambroxol as a pharmacological chaperone for mutant glucocerebrosidase.Blood cells, molecules & diseases · 2013Article
- Article
- Discovery, structure-activity relationship, and biological evaluation of noninhibitory small molecule chaperones of glucocerebrosidase.Journal of medicinal chemistry · 2012Article
- Non-iminosugar glucocerebrosidase small molecule chaperones.MedChemComm · 2012Article
- Histone deacetylase inhibitors prevent the degradation and restore the activity of glucocerebrosidase in Gaucher disease.Proceedings of the National Academy of Sciences of the United States of America · 2011Article
- Binding of 3,4,5,6-tetrahydroxyazepanes to the acid-β-glucosidase active site: implications for pharmacological chaperone design for Gaucher disease.Biochemistry · 2011Article
- Chemical and biological approaches for adapting proteostasis to ameliorate protein misfolding and aggregation diseases: progress and prognosis.Cold Spring Harbor perspectives in biology · 2011Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Gaucher disease, resulting from deficient lysosomal glucocerebrosidase (GC) activity, is the most common lysosomal storage disorder. Clinically important GC mutant enzymes typically have reduced specific activity and reduced lysosomal concentration, the latter due to compromised folding and trafficking. We and others have demonstrated that pharmacological chaperones assist variant GC folding by binding to the active site, stabilizing the native conformation of GC in the neutral pH environment of the endoplasmic reticulum (ER), enabling its trafficking from the ER to the Golgi and on to the lysosome. The mutated GC fold is generally stable in the lysosome after pharmacological chaperone dissociation, owing to the low pH environment for which the fold was evolutionarily optimized and the high substrate concentration, enabling GC to hydrolyze glucosylceramide to glucose and ceramide. The hypothesis of this study was that we could combine GC pharmacological chaperone structure-activity relationships from distinct chemical series to afford potent novel chaperones comprising a carbohydrate-like substructure that binds in the active site with a hydrophobic substructure that binds in a nearby pocket. We combined isofagomine and 2,5-anhydro-2,5-imino-D-glucitol active site binding substructures with hydrophobic alkyl adamantyl amides to afford novel small molecules with enhanced ability to increase GC activity in patient-derived fibroblasts. The cellular activity of N370S and G202R GC in fibroblasts is increased by 2.5- and 7.2-fold with isofagmine-based pharmacological chaperones N-adamantanyl-4-((3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)piperidin-1-yl)-butanamide (3) and N-adamantanyl-4-((3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)piperidin-1-yl)pentanamide (4), respectively, the best enhancements observed to date.
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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.