Design, synthesis and evaluation of protein disulfide isomerase inhibitors with nitric oxide releasing activity

Lin Li; Jian Liu; Yaqi Ding; Zhenxiong Shi; Bo Peng; Naidi Yang; Danqi Hong; Chengwu Zhang; Chuanhao Yao; Jingyan Ge; Wei Huang

doi:10.1016/j.bmcl.2019.126898

Design, synthesis and evaluation of protein disulfide isomerase inhibitors with nitric oxide releasing activity

Bioorg Med Chem Lett. 2020 Feb 1;30(3):126898. doi: 10.1016/j.bmcl.2019.126898. Epub 2019 Dec 17.

Authors

Lin Li¹, Jian Liu², Yaqi Ding³, Zhenxiong Shi⁴, Bo Peng⁴, Naidi Yang³, Danqi Hong², Chengwu Zhang³, Chuanhao Yao⁴, Jingyan Ge⁵, Wei Huang⁶

Affiliations

¹ Shaanxi Institute of Flexible Electronics (SIFE), Northwestern Polytechnical University (NPU), 127 West Youyi Road, Xi'an 710072, PR China. Electronic address: iamlli@nwpu.edu.cn.
² Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310014, PR China.
³ Key Laboratory of Flexible Electronics (KLOFE) & Institute of Advanced Materials (IAM), Nanjing Tech University (Nanjing Tech), 30 South Puzhu Road, Nanjing 211800, PR China.
⁴ Shaanxi Institute of Flexible Electronics (SIFE), Northwestern Polytechnical University (NPU), 127 West Youyi Road, Xi'an 710072, PR China.
⁵ Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310014, PR China. Electronic address: gejy@zjut.edu.cn.
⁶ Shaanxi Institute of Flexible Electronics (SIFE), Northwestern Polytechnical University (NPU), 127 West Youyi Road, Xi'an 710072, PR China; Key Laboratory of Flexible Electronics (KLOFE) & Institute of Advanced Materials (IAM), Nanjing Tech University (Nanjing Tech), 30 South Puzhu Road, Nanjing 211800, PR China.

PMID: 31874828
DOI: 10.1016/j.bmcl.2019.126898

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.

Keywords: Biotin-switch technique; Nitric oxide; Protein disulfide isomerase; S-nitrosylation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Catalytic Domain
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Drug Design*
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology
Humans
Molecular Docking Simulation
Nitric Oxide / metabolism*
Nitric Oxide Donors / chemistry*
Nitric Oxide Donors / metabolism
Nitric Oxide Donors / pharmacology
Protein Disulfide-Isomerases / antagonists & inhibitors*
Protein Disulfide-Isomerases / metabolism

Substances

Enzyme Inhibitors
Nitric Oxide Donors
Nitric Oxide
Protein Disulfide-Isomerases