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.