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

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

Institute of Flexible Electronics

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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.

Original language	English
Article number	126898
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	30
Issue number	3
DOIs	https://doi.org/10.1016/j.bmcl.2019.126898
State	Published - 1 Feb 2020

Keywords

Biotin-switch technique
Nitric oxide
Protein disulfide isomerase
S-nitrosylation

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@article{08af4a9ec6c54635b2467813ad500207,

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

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",

author = "Lin Li and Jian Liu and Yaqi Ding and Zhenxiong Shi and Bo Peng and Naidi Yang and Danqi Hong and Chengwu Zhang and Chuanhao Yao and Jingyan Ge and Wei Huang",

note = "Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",

year = "2020",

month = feb,

day = "1",

doi = "10.1016/j.bmcl.2019.126898",

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T1 - Design, synthesis and evaluation of protein disulfide isomerase inhibitors with nitric oxide releasing activity

AU - Li, Lin

AU - Liu, Jian

AU - Ding, Yaqi

AU - Shi, Zhenxiong

AU - Peng, Bo

AU - Yang, Naidi

AU - Hong, Danqi

AU - Zhang, Chengwu

AU - Yao, Chuanhao

AU - Ge, Jingyan

AU - Huang, Wei

PY - 2020/2/1

Y1 - 2020/2/1

N2 - 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.

AB - 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.

KW - Biotin-switch technique

KW - Nitric oxide

KW - Protein disulfide isomerase

KW - S-nitrosylation

UR - https://www.scopus.com/pages/publications/85076839031

U2 - 10.1016/j.bmcl.2019.126898

DO - 10.1016/j.bmcl.2019.126898

M3 - 文章

C2 - 31874828

AN - SCOPUS:85076839031

SN - 0960-894X

VL - 30

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 3

M1 - 126898

ER -

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

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Keywords

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