ArticleBiochimica et biophysica acta. General subjects2017
Establishment of a suite of assays that support the discovery of proteasome stimulators.
Article in Biochimica et biophysica acta. General subjects, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 62 citations in OpenAlex.
- Stimulating proteasomal degradation in human proteinopathies.The FEBS journal · 2026Review
- Novel Small-Molecule Analogues of IU1 Ameliorate Amyloid-β Mediated Toxicity in Alzheimer's Disease Cell and Worm Models.International journal of molecular sciences · 2026Article
- Recent Advancements in 20S Proteasome Enhancement: Degradation of Undruggable Targets.ACS medicinal chemistry letters · 2025Review
- Targeted Degradation of Histone Deacetylases via Bypassing E3 Ligase Targeting Chimeras (BYETACs).ACS medicinal chemistry letters · 2025Article
- Peptidomimetics Activating the Proteasome: A New Perspective for Parkinson's Treatment.Journal of medicinal chemistry · 2025Article
- Proteasome: Role in T Cell Function Regulation.International journal of biological sciences · 2025Review
- Understanding neurodevelopmental proteasomopathies as new rare disease entities: A review of current concepts, molecular biomarkers, and perspectives.Genes & diseases · 2024Review
- Pilot-Scale Screening of Clinically Approved Drugs to Identify Uridine Insertion/Deletion RNA Editing Inhibitors inACS infectious diseases · 2024Article
- 20S proteasome enhancers prevent cytotoxic tubulin polymerization-promoting protein induced α-synuclein aggregation.iScience · 2024Article
- Rpt5-Derived Analogs Stimulate Human Proteasome Activity in Cells and Degrade Proteins Forming Toxic Aggregates in Age-Related Diseases.International journal of molecular sciences · 2024Article
- Discovery and Development of Cyclic Peptide Proteasome Stimulators.Chembiochem : a European journal of chemical biology · 2024Article
- Proteasome Activators and Ageing: Restoring Proteostasis Using Small Molecules.Sub-cellular biochemistry · 2024Review
- Oleuropein enhances proteasomal activity and reduces mutant huntingtin-induced cytotoxicity.Frontiers in pharmacology · 2024Article
- Proteasome localization and activity in pig brain andFrontiers in cellular neuroscience · 2024Article
- Targeting Proteasomes and the MHC Class I Antigen Presentation Machinery to Treat Cancer, Infections and Age-Related Diseases.Cancers · 2023Review
- Proteasomal Stimulation by MK886 and Its Derivatives Can Rescue Tau-Induced Neurite Pathology.Molecular neurobiology · 2023Article
- Development of a Cell-Based AlphaLISA Assay for High-Throughput Screening for Small Molecule Proteasome Modulators.ACS omega · 2023Article
- Oleic amide derivatives as small molecule stimulators of the human proteasome's core particle.RSC medicinal chemistry · 2022Article
- Biology of the Extracellular Proteasome.Biomolecules · 2022Review
- Small Molecule 20S Proteasome Enhancer Regulates MYC Protein Stability and Exhibits Antitumor Activity in Multiple Myeloma.Biomedicines · 2022Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
backgroundThe proteasome catalyzes the degradation of many mis-folded proteins, which are otherwise cytotoxic. There is interest in the discovery of proteasome agonists, but previous efforts to do so have been disappointing.
methodsThe cleavage of small fluorogenic peptides is used routinely as an assay to screen for proteasome modulators. We have developed follow-on assays that employ more physiologically relevant substrates.
resultsTo demonstrate the efficacy of this workflow, the NIH Clinical Collection (NCC) was screened. While many compounds stimulated proteasome-mediated proteolysis of the pro-fluorogenic peptide substrates, most failed to evince activity in assays with larger peptide or protein substrates. We also show that two molecules claimed previously to be proteasome agonists, oleuropein and betulinic acid, indeed accelerate hydrolysis of the fluorogenic substrate, but have no effect on the turnover of a mis-folded protein in vitro or in cellulo. However, two small molecules from the NCC, MK-866 and AM-404, stimulate the proteasome-mediated turnover of a mis-folded protein in living cells by 3- to 4-fold.
conclusionAssays that monitor the proteasome-mediated degradation of larger peptides and proteins can distinguish bona fide agonists from compounds only able to stimulate the cleavage of short, non-physiologically relevant peptides. GENERAL SIGNIFICANCE: A suite of assays has been established that allows the discovery of bona fide proteasome agonists. AM-404 and MK-866 can be useful tools for cell culture experiments, and can serve as scaffolds to generate more potent 20S stimulators.
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