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Last update 08 May 2025

PDIA4

Last update 08 May 2025

Basic Info

Synonyms

Endoplasmic reticulum resident protein 70, Endoplasmic reticulum resident protein 72, ER protein 70

+ [7]

Introduction-

Drugs associated with PDIA4

PS-001

Target

PDIA4

Mechanism

PDIA4 inhibitors

Active Org.

Pharmasaga

Originator Org.

Pharmasaga

Active Indication

Diabetes Mellitus, Type 2 [+1]

Inactive Indication-

Drug Highest PhasePhase 1

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

PS-002

Target

PDIA4

Mechanism

PDIA4 inhibitors

Active Org.

Pharmasaga

Originator Org.

Pharmasaga

Active Indication

Autoimmune Diseases

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with PDIA4

NCT05176210

/ RecruitingPhase 1

A Phase I, Double-Blind, Placebo-Controlled, Randomized, Single- and Multiple-Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Food Effect and Potential Efficacy of PS1 in Subjects

This is a phase I, double-blind, placebo-controlled, randomized, single- and multiple-ascending dose study to evaluate new study intervention, PS1. PS1 is a potential blood glucose control medication, which is developed by Pharmasaga Co. Ltd. planned for treating type II diabetes mellitus (T2DM). This is a first-in-human study to evaluate the safety, tolerability, pharmacokinetics (PK), food effect and potential efficacy of PS1 in subjects.

Start Date22 Dec 2023

Sponsor / Collaborator-

100 Clinical Results associated with PDIA4

100 Translational Medicine associated with PDIA4

0 Patents (Medical) associated with PDIA4

256

Literatures (Medical) associated with PDIA4

01 Mar 2025·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

PDIA4 targets IRE1α/sXBP1 to alleviate NLRP3 inflammasome activation and renal tubular injury in diabetic kidney disease

Article

Author: Wang, Dekun ; Zhang, Zhujun ; Liu, Xuan ; Zhang, Yuying ; Su, Yu ; Zhou, Donghui ; Zhang, Mianzhi ; Shen, Tianyu ; Mi, Xue ; Su, Qiuyue ; Yue, Shijing ; Tan, Xiaoyue ; Liu, Hongling

The role of ER stress in the pathogenesis of diabetic kidney diseases (DKD) remains unclear. We employed bioinformatics to identify the UPR pathway activation, inflammation, and programmed cell death patterns in diabetic tubules. Levels of IRE1α/sXBP1 signaling, NLRP3 inflammasome activity and pyroptosis in tubular cells under high glucose conditions were measured. IRE1α knockdown was used to determine its role in glucose-triggered activation of the NLRP3 inflammasome and pyroptosis. PDIA4 overexpression and silencing were used to assess its impact on the IRE1α/sXBP1 pathway. The dynamic interaction among PDIA4, GRP78, and IRE1α under high glucose were analyzed using immunoprecipitation and crosslinking assays. In STZ-induced and db/db mouse models of DKD, the regulatory role of PDIA4 on IRE1α/sXBP1 signaling and diabetic tubular inflammation and injury were evaluated. Our study showed that IRE1α/sXBP1, NLRP3 inflammasome, and pyroptosis are activated in the renal tubules of DKD patients. Induction of IRE1α pathway mediated the glucose-triggered activation of the NLRP3 inflammasome and pyroptosis. Moreover, overexpression of PDIA4 decreased the activation of IRE1α/sXBP1 under high glucose conditions. High glucose leads to the release of GRP78 from IRE1α and an increased interaction between IRE1α and PDIA4. In mouse models of DKD, overexpressing PDIA4 mitigated diabetic tubular injury and inflammation, marked by decreased IRE1α/sXBP1 and NLRP3 inflammasome. In conclusion, our findings demonstrate that high glucose triggers NLRP3 inflammasome and pyroptosis via the IRE1α/sXBP1 pathway in renal tubular cells. Overexpression of PDIA4 suppresses IRE1α signaling by binding to its oligomeric form, implying a promising therapeutic intervention for DKD.

01 Feb 2025·Journal of Thrombosis and Haemostasis

Galloylated polyphenols represent a new class of antithrombotic agents with broad activity against thiol isomerases

Article

Author: Yang, Moua ; Xie, Huanzhang ; Sack, Kelsey D ; Bekendam, Roelof H ; Levy, Oren ; Ghiran, Ionita C ; Flaumenhaft, Robert ; Kennedy, Quinn P ; Guo, Shihui ; Owegie, Osamede C ; Hancco Zirena, Ivan ; Lin, Lin ; Fulcidor, Emmy ; Merrill-Skoloff, Glenn ; Scartelli, Christina ; Patel, Anika

BACKGROUNDBoth protein disulfide isomerase (PDI) and SARS-CoV-2 main protease (M^pro) are reliant on active-site cysteines stabilized by adjacent amino acids. We reasoned that redox-active compounds might interfere with both enzymes by acting in the vicinity of these reactive sites thus interfering with viral replication and thrombus formation. Our previous screen of 1019 flavonoids identified several compounds that inhibit SARS-CoV-2 M^pro.OBJECTIVESOur goal was to identify phytochemical inhibitors of SARS-CoV-2 M^pro that block thiol isomerases and are antithrombotic.METHODSPDI, ERp57, ERp5, ERp46, isolated domains of PDI, and PDI mutants were used to evaluate the effects of galloylated polyphenols and their analogs on thiol isomerase reductase activity. Laser-injury and ferric chloride models of thrombus formation and a tail snip assay were used to assess the effects on thrombosis and hemostasis.RESULTSPinocembrin 7-O-(3''-galloyl-4'',6''-(S)-hexahydroxydiphenoyl)-β-D-glucose (PGHG) inhibited both PDI and SARS-CoV-2 M^pro. Evaluation of isolated PDI fragments and active-site cysteine mutants showed that PGHG acts at the catalytic domains. Structure-function studies showed that PGHG interacts with histidines within the Cys53-Gly54-His55-Cys56 motifs of PDI. PGHG was equally active against other thiol isomerases, including ERp57, ERp5, ERp72, and ERp46. Screening numerous galloylated polyphenols demonstrated a class effect on thiol isomerase inhibition. Structure-activity relationships indicated that the galloyl moieties within large galloylated polyphenols were important for their inhibitory activity. PGHG and punicalagin were antithrombotic in murine models of thrombus formation.CONCLUSIONSGalloylated polyphenols represent a large class of antithrombotic compounds with broad activity against thiol isomerases. Many of these compounds also inhibit SARS-CoV-2 M^pro and viral replication.

01 Feb 2025·Research and Practice in Thrombosis and Haemostasis

Thiol isomerase ERp18 enhances platelet activation and arterial thrombosis

Article

Author: Han, Yue ; Jiang, Miao ; He, Chao ; Lv, Keyu ; Zhang, Jingyu ; Wu, Depei ; Wu, Yi ; Fang, Chao ; Zhao, Zhenzhen ; Yang, Aizhen ; Lu, Yi ; Zhang, Yuxin

BackgroundThiol isomerases regulate the thiol-disulfide exchange of functional proteins in cells. Using genetically modified mouse models and inhibitors, we and others demonstrated that 7 thiol isomerases (ERp57, protein diisulfide isomerase, ERp72, ERp46, ERp5, TMX4, and TMX1) participate in thrombosis. There are 21 thiol isomerases in mammals, but whether other enzymes of this family also contribute to thrombosis remains unknown.ObjectivesInvestigate whether and how ERp18 participates in arterial thrombosis.MethodsERp18 knockout mice and arterial thrombosis models were used to determine the role of ERp18 in thrombosis. Platelets from ERp18 knockout mice were used to detect aggregation, activation, spreading, and clot retraction. Finally, flow cytometry and immunoprecipitation were used to detect the binding between ERp18 and α_IIbβ₃.ResultsThe mice lacking ERp18 exhibited a prolonged tail bleeding time and decreased platelet thrombus formation in FeCl₃-induced carotid arterial injury and laser-induced cremaster artery injury models. ERp18 deficiency inhibited platelet aggregation, adenosine triphosphate release, integrin α_IIbβ₃ activation, P-selectin expression, platelet adhesion, as well as clot retraction. Flow cytometry and coimmunoprecipitation analyses revealed that ERp18 binds to the platelet surface via interaction with integrin α_IIbβ₃. Moreover, the ERp18 protein promoted the binding of integrin α_IIbβ₃ to fibrinogen and platelet aggregation. Furthermore, the recombinant ERp18 protein exhibited reductase activity and cleaved integrin α_IIbβ₃ disulfides.ConclusionERp18 participates in platelet activation and thrombosis. Its function is, at least in part, through the regulation of integrin α_IIbβ₃ function. This finding expands our understanding of the role of thiol isomerases in the redox regulation of thrombosis and platelet function.

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PDIA4

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