Design,synthesis and evaluation of protein disulfide isomerase inhibitors with nitric oxide releasing activity |
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| Affiliation: | 1. State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Center for R&D of Fine Chemicals of Guizhou University, Guiyang 550025, China;2. State Key Lab of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China;1. Medicinal Chemistry & Biotechnology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India;2. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India;3. Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India;4. CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500 007, India;5. School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi 110 062, India;1. State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China;2. Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China;3. Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, University Park Campus, Nottingham NG7 2RD, UK;1. Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, PR China;2. School of Food Sciences and Engineering, South China University of Technology, Guangzhou 510641, China;3. Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, PR China;4. Department of Allergy, The Third Affiliated Hospital of Shenzhen University, Shenzhen 518020, PR China |
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| Abstract: | ![]()
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. |
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| Keywords: | Protein disulfide isomerase S-nitrosylation Nitric oxide Biotin-switch technique |
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