Design, synthesis and evaluation of protein disulfide isomerase inhibitors with nitric oxide releasing activity
| Autor: | Chuanhao Yao, Lin Li, Naidi Yang, Bo Peng, Wei Huang, Jingyan Ge, Jian Liu, Chengwu Zhang, Yaqi Ding, Zhenxiong Shi, Danqi Hong |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
inorganic chemicals
Cell Survival medicine.medical_treatment Clinical Biochemistry Protein Disulfide-Isomerases Pharmaceutical Science Nitric Oxide 01 natural sciences Biochemistry Nitric oxide HeLa chemistry.chemical_compound Catalytic Domain Cell Line Tumor Drug Discovery medicine Humans Nitric Oxide Donors Enzyme Inhibitors Protein disulfide-isomerase Molecular Biology Cell Proliferation Binding Sites biology 010405 organic chemistry Chemistry Insulin Endoplasmic reticulum Organic Chemistry S-Nitrosylation biology.organism_classification Fluorescence nervous system diseases 0104 chemical sciences Molecular Docking Simulation body regions 010404 medicinal & biomolecular chemistry Drug Design Molecular Medicine Protein folding |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 30:126898 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2019.126898 |
| Popis: | Protein disulfide isomerase (PDI), a chaperone protein mostly in endoplasmic reticulum, catalyzes disulfide bond breakage, formation, and rearrangement to promote protein folding. PDI is regarded as a new target for treatment of several disorders. Here, based on the combination principle, we report a new PDI reversible modulator 16F16A-NO by replacing the reactive group in a known PDI inhibitor 16F16 with nitric oxide (NO) donor. Using molecular docking experiment, 16F16A-NO could embed into the active cavity of PDI. From newly developed fluorescent assay, 16F16A-NO showed rapid NO release. Furthermore, it is capable to moderately inhibit activity of PDI and S-nitrosylate the protein, indicating by insulin aggregation assay and biotin-switch technique. Finally, it displayed a dose-dependent antiproliferative activity against SH-SY5Y and HeLa tumor cells. Our designed hybrid compound 16F16A-NO showed a reasonable activity and might offer a promising avenue to develop novel PDI inhibitors for disease treatments. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect