TY - JOUR
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
N1 - Publisher Copyright:
© 2019 Elsevier Ltd
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 - http://www.scopus.com/inward/record.url?scp=85076839031&partnerID=8YFLogxK
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 -