ArticleProceedings of the National Academy of Sciences of the United States of America2015
Small molecule-induced oxidation of protein disulfide isomerase is neuroprotective.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
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Who cites it
64 citing papers in PubMed, 104 citations in OpenAlex.
- Molecular mechanisms of protein disulfide isomerase antagonism by punicalagin.Biochemical and biophysical research communications · 2026Article
- Article
- Enzyme-Inspired Design of Redox-Active Molecules for Promotion of Oxidative Protein Folding.Chembiochem : a European journal of chemical biology · 2026Review
- Pharmacological targeting of the NLRP3 LRR domain with isothiazolinones overcomes CRID3-resistant inflammation.EMBO molecular medicine · 2026Article
- Molecular insights into protein disulfide isomerase antagonism by punicalagin.bioRxiv : the preprint server for biology · 2026Article
- Tannic acid inhibits TNF-α signaling by targeting the protein disulfide isomerase and alleviates symptoms in an imiquimod-induced psoriasis mouse model.Cell communication and signaling : CCS · 2025Article
- Rapid Functional Drug Screening of Passage-Zero Patient Brain Tumor Tissues Ex Vivo: Results from a Clinical Feasibility Study.Research square · 2025Article
- Extracellular PDI in thrombosis and vascular injury.Thrombosis journal · 2025Review
- DR5 Disulfide Bonding Functions as a Sensor and Effector of Protein Folding Stress.Molecular cancer research : MCR · 2025Article
- A novel neuroprotective mechanism of selegiline by suppressing the pro-apoptotic activity of protein disulfide isomerase.Molecular biomedicine · 2025Article
- CaCommunications chemistry · 2025Article
- Erp57 facilitates ZIKV-induced DNA damage via NS2B/NS3 complex formation.Emerging microbes & infections · 2024Article
- Mechanism of RSL3-induced ferroptotic cell death in HT22 cells: crucial role of protein disulfide isomerase.Acta biochimica et biophysica Sinica · 2024Article
- Endoplasmic reticulum stress-a key guardian in cancer.Cell death discovery · 2024Review
- Inclusive Pattern Generation Protocols to Decode Thiol-Mediated Uptake.ACS central science · 2024Article
- The small molecule CBR-5884 inhibits themBio · 2024Article
- Integrated Transcriptome and Proteome Analysis Reveals the Regulatory Mechanism of Root Growth by Protein Disulfide Isomerase in Arabidopsis.International journal of molecular sciences · 2024Article
- Pan-Inhibition of Protein Disulfide Isomerase Caused Cell Death through Disrupting Cellular Proteostasis in Pancreatic Ductal Adenocarcinoma Cells.International journal of molecular sciences · 2023Article
- Pervasive aggregation and depletion of host and viral proteins in response to cysteine-reactive electrophilic compounds.bioRxiv : the preprint server for biology · 2023Article
- Sulfenylation links oxidative stress to protein disulfide isomerase oxidase activity and thrombus formation.Journal of thrombosis and haemostasis : JTH · 2023Article
4 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 4 institutions in 1 country.
Funding
Abstract
Protein disulfide isomerase (PDI) is a chaperone protein in the endoplasmic reticulum that is up-regulated in mouse models of, and brains of patients with, neurodegenerative diseases involving protein misfolding. PDI's role in these diseases, however, is not fully understood. Here, we report the discovery of a reversible, neuroprotective lead optimized compound (LOC)14, that acts as a modulator of PDI. LOC14 was identified using a high-throughput screen of ∼10,000 lead-optimized compounds for potent rescue of viability of PC12 cells expressing mutant huntingtin protein, followed by an evaluation of compounds on PDI reductase activity in an in vitro screen. Isothermal titration calorimetry and fluorescence experiments revealed that binding to PDI was reversible with a Kd of 62 nM, suggesting LOC14 to be the most potent PDI inhibitor reported to date. Using 2D heteronuclear single quantum correlation NMR experiments, we were able to map the binding site of LOC14 as being adjacent to the active site and to observe that binding of LOC14 forces PDI to adopt an oxidized conformation. Furthermore, we found that LOC14-induced oxidation of PDI has a neuroprotective effect not only in cell culture, but also in corticostriatal brain slice cultures. LOC14 exhibited high stability in mouse liver microsomes and blood plasma, low intrinsic microsome clearance, and low plasma-protein binding. These results suggest that LOC14 is a promising lead compound to evaluate the potential therapeutic effects of modulating PDI in animal models of disease.
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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.