Route Exploration and Synthesis of the Reported Pyridone-Based PDI Inhibitor STK076545

Enzyme Protein ◽

Allyl Ester ◽

Disulfide Isomerase ◽

X Ray ◽

Surface Receptors ◽

Promising Target ◽

Biological Studies ◽

Final Compound ◽

The enzyme protein disulfide isomerase (PDI) is essential for the correct folding of proteins and the activation of certain cell surface receptors, and is a promising target for the treatment of cancer and thrombotic conditions. A previous high-throughput screen identified the commercial compound STK076545 as a promising PDI inhibitor. To confirm its activity and support further biological studies, a resynthesis was pursued of the reported b-keto-amide with an N-alkylated pyridone at the a-position. Numerous conventional approaches were complicated by undesired fragmentations or rearrangements. However, a successful 5-step synthetic route was achieved using an aldol reaction with an a-pyridone allyl ester as a key step. An X-ray crystal structure of the final compound confirmed that the reported structure of STK076545 was achieved, however its lack of PDI activity and inconsistent spectral data suggest that the commercial structure was misassigned.

Identification and Characterization of a Novel Protein Disulfide Isomerase Gene (MgPDI2) from Meloidogyne graminicola

International Journal of Molecular Sciences ◽

10.3390/ijms21249586 ◽

2020 ◽

Vol 21 (24) ◽

pp. 9586

Author(s):

Zhongling Tian ◽

Zehua Wang ◽

Maria Munawar ◽

Jingwu Zheng

Keyword(s):

Cell Death ◽

Catalytic Domain ◽

Root Knot Nematode ◽

Transient Expression Assay ◽

Disulfide Isomerase ◽

Meloidogyne Graminicola ◽

Promising Target ◽

Nematode Parasitism ◽

Protein disulfide isomerase (PDI) is a multifunctional enzyme that catalyzes rate-limiting reactions such as disulfide bond formation, isomerization, and reduction. There is some evidence that indicates that PDI is also involved in host-pathogen interactions in plants. In this study, we show that the rice root-knot nematode, Meloidogyne graminicola, has evolved a secreted effector, MgPDI2, which is expressed in the subventral esophageal glands and up-regulated during the early parasitic stage of M. graminicola. Purified recombinant MgPDI2 functions as an insulin disulfide reductase and protects plasmid DNA from nicking. As an effector, MgPDI2 contributes to nematode parasitism. Silencing of MgPDI2 by RNA interference in the pre-parasitic second-stage juveniles (J2s) reduced M. graminicola multiplication and also increased M. graminicola mortality under H2O2 stress. In addition, an Agrobacterium-mediated transient expression assay found that MgPDI2 caused noticeable cell death in Nicotiana benthamiana. An intact C-terminal region containing the first catalytic domain (a) with an active motif (Cys-Gly-His-Cys, CGHC) and the two non-active domains (b and b′) is required for cell death induction in N. benthamiana. This research may provide a promising target for the development of new strategies to combat M. graminicola infections.

Correlation between antibodies to bisphenol A, its target enzyme protein disulfide isomerase and antibodies to neuron-specific antigens

Journal of Applied Toxicology ◽

10.1002/jat.3383 ◽

2016 ◽

Vol 37 (4) ◽

pp. 479-484 ◽

Cited By ~ 7

Author(s):

Datis Kharrazian ◽

Aristo Vojdani

Keyword(s):

Bisphenol A ◽

Enzyme Protein ◽

Disulfide Isomerase ◽

Specific Antigens ◽

Protein Disulfide ◽

Target Enzyme

Protein disulfide isomerase: a promising target for cancer therapy

Drug Discovery Today ◽

10.1016/j.drudis.2013.10.017 ◽

2014 ◽

Vol 19 (3) ◽

pp. 222-240 ◽

Cited By ~ 118

Author(s):

Shili Xu ◽

Saranya Sankar ◽

Nouri Neamati

Keyword(s):

Cancer Therapy ◽

Disulfide Isomerase ◽

Promising Target ◽

Platelet protein disulfide isomerase is localized in the dense tubular system and does not become surface expressed after activation

Blood ◽

10.1182/blood-2009-03-210450 ◽

2009 ◽

Vol 114 (21) ◽

pp. 4738-4740 ◽

Cited By ~ 18

Author(s):

Hezder E. van Nispen tot Pannerden ◽

Suzanne M. van Dijk ◽

Vivian Du ◽

Harry F. G. Heijnen

Keyword(s):

Cell Surface ◽

Active Conformation ◽

Enzyme Protein ◽

Disulfide Isomerase ◽

Anionic Phospholipids ◽

Platelet Protein ◽

Activated Platelets ◽

Tubular System ◽

Abstract Evidence is accumulating that circulating tissue factor (TF) contributes to the initiation of coagulation and the formation of fibrin. The majority of circulating TF is cryptic, and it has been suggested that close vicinity with anionic phospholipids on the cell surface increases the active conformation of TF. Two recent papers have shown that encryption of TF and initiation of coagulation are facilitated by the enzyme protein disulfide isomerase (PDI), possibly on the surface of activated platelets or endothelial cells. In this brief report, we demonstrate that the majority of PDI in platelets is intracellular where it is exclusively located in the dense tubular system. On activation, PDI remains confined to the intracellular stores of the dense tubular system and is neither released nor targeted to the cell surface. Similar results were obtained in endothelium where PDI remains exclusively localized in the endoplasmic reticulum, both at steady state and after thrombin stimulation.