Quercetin 3, 3′, 4′, 5, 7-O- pentasulfate (QPS): A novel activator of protein disulfide isomerase

Khan, Abdul Burhan; Gupta, Neha; Rashid, Qudsia; Ahmad, Irshad; Bano, Shadabi; U, Siddiqui; Abid, Mohammad; Jairajpuri, Mohamad Aman

doi:10.1016/j.medidd.2020.100029

Cited by 5 publications

(4 citation statements)

References 20 publications

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“…Compounds 1−8 were evaluated for their PDI inhibitory activities in an insulin-based turbidity assay (Tables 1, S4, and Figure S15). 6,27 Inhibitors 1, 2, and 4 showed nanomolar inhibitory activities with IC 50 values of 0.15 ± 0.04, 0.23 ± 0.03, and 0.50 ± 0.15 μM, respectively, which are about 41.8, 20.9, and 12.5 times lower than that of isoquercetin (the positive control), 12 respectively. Compounds 3, 5, and 6 were also active, but at micromolar potencies similar to isoquercetin, while, 7 and 8 did not show inhibitory effects (IC 50 > 100 μM).…”

Section: ■ Results and Discussionmentioning

confidence: 96%

Piericones A and B as Potent Antithrombotics: Nanomolar Noncompetitive Protein Disulfide Isomerase Inhibitors with an Unexpected Chemical Architecture

Zheng

Huang

et al. 2023

J. Am. Chem. Soc.

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Extracellular protein disulfide isomerase (PDI) is a promising target for thrombotic-related diseases. Four potent PDI inhibitors with unprecedented chemical architectures, piericones A–D (1–4), were isolated from Pieris japonica. Their structures were elucidated by spectroscopic data analysis, chemical methods, quantum 13C nuclear magnetic resonance DP4+ and electronic circular dichroism calculations, and single-crystal X-ray diffraction analysis. Piericones A (1) and B (2) were nanomolar noncompetitive PDI inhibitors possessing an unprecedented 3,6,10,15-tetraoxatetracyclo[7.6.0.04,9.01,12]pentadecane motif with nine contiguous stereogenic centers. Their biosynthetic pathways were proposed to include a key intermolecular aldol reaction and an intramolecular 1,2-migration reaction. Piericone A (1) significantly inhibited in vitro platelet aggregation and fibrin formation and in vivo thrombus formation via the inhibition of extracellular PDI without increasing the bleeding risk. The molecular docking and dynamics simulation of 1 and 2 provided a novel structure basis to develop PDI inhibitors as potent antithrombotics.

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Section: ■ Results and Discussionmentioning

confidence: 96%

Piericones A and B as Potent Antithrombotics: Nanomolar Noncompetitive Protein Disulfide Isomerase Inhibitors with an Unexpected Chemical Architecture

Zheng

Huang

et al. 2023

J. Am. Chem. Soc.

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“…In this study, we have tried to understand the molecular basis of PDI regulation of ATIII, a major anticoagulant protein of the serine protease inhibitor family (serpins). In a prior study, we presented the development of a derivative of quercetin (QPS) that exhibited a remarkable ability to substantially enhance the activity of PDI [ 29 ]. To determine the direct impact of PDI on the coagulation cascade, we conducted coagulation assays (APTT, PT, and TT) using its activator (QPS) and inhibitor (Q3R).…”

Section: Discussionmentioning

confidence: 99%

Protein disulfide isomerase uses thrombin–antithrombin complex as a template to bind its target protein and alter the blood coagulation rates

Khan,

Siddiqui,

Fatima

et al. 2024

Bioscience Reports

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During inflammation and situations of cellular stress Protein Disulfide Isomerase (PDI) is released in the blood plasma from the platelet and endothelial cells to influence thrombosis. The addition of exogenous PDI makes the environment pro-thrombotic by inducing disulfide bond formation in specific plasma protein targets like vitronectin, factor V, and factor XI. However, the mechanistic details of PDI interaction with its target remain largely unknown. A decrease in the coagulation time was detected in activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) in addition to the purified recombinant PDI (175nM). The coagulation time can be controlled using an activator (quercetin penta sulfate, QPS) or an inhibitor (Quercetin 3-rutinoside, Q3R) of PDI activity. Likewise, the PDI variants that increase the PDI activity (H399R) decrease, and the variant with low activity (C53A) increases the blood coagulation time. An SDS-PAGE and western blot analysis showed that the PDI does not form a stable complex with either thrombin or Antithrombin (ATIII) but it uses the ATIII-thrombin complex as a template to bind and maintain its activity. A complete inhibition of thrombin activity on the formation of ATIII-thrombin-PDI complex, and the complex-bound PDI-catalyzed disulfide bond formation of the target proteins may control the pro- and anti-thrombotic role of PDI.

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“…This structural feature is quite different from that of PDIA1. Please do not adjust margins Please do not adjust margins about an enhancer of PDIs activity 16 . Regarding thiol compoundmediated catalytic activity 17 , developing novel thiol compounds to target cysteines within CxxC motifs could be extremely effective.…”

Section: Boosting the Enzymatic Activity Of Cxxc Motif-containing Pdi...mentioning

confidence: 99%

“…However, in the case of PDIA1, an allosteric switch of its substrate-binding pocket increases its catalytic activity; 13 yet, only a few studies were reported about an enhancer of PDIs activity. 16 Regarding thiol compound-mediated catalytic activity, 17 developing novel thiol compounds to target cysteines within CxxC motifs could be extremely effective.…”

mentioning

confidence: 99%

Boosting the enzymatic activity of CxxC motif-containing PDI family members

Kuramochi,

Yamashita,

Arai

et al. 2024

Chem. Commun.

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Quercetin 3, 3′, 4′, 5, 7-O- pentasulfate (QPS): A novel activator of protein disulfide isomerase

Cited by 5 publications

References 20 publications

Piericones A and B as Potent Antithrombotics: Nanomolar Noncompetitive Protein Disulfide Isomerase Inhibitors with an Unexpected Chemical Architecture

Piericones A and B as Potent Antithrombotics: Nanomolar Noncompetitive Protein Disulfide Isomerase Inhibitors with an Unexpected Chemical Architecture

Protein disulfide isomerase uses thrombin–antithrombin complex as a template to bind its target protein and alter the blood coagulation rates

Boosting the enzymatic activity of CxxC motif-containing PDI family members

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