# Identification of an inhibitor of PDI-GPIbalpha signaling as a novel antithromboinflammatory agent

> **NIH NIH R33** · WASHINGTON UNIVERSITY · 2021 · $551,250

## Abstract

Project Summary
Thromboinflammatory diseases, including atherothrombosis, stroke and peripheral vasculitis, result in >30% of
all deaths globally. Underlying the pathology of thromboinflammation is increased adhesiveness of platelets and
leukocytes. Although many antiplatelet and anti-inflammatory therapies have been used for disease treatment,
these drugs increase the risk of major bleeding or impair immune responses. Using protein disulfide isomerase
(PDI) conditional knockout (CKO) mice and inhibitors, we and others have shown that extracellular PDI is crucial
for platelet thrombus formation in arterial thrombosis and neutrophil recruitment to inflamed endothelium in
vascular inflammation. However, inhibition of extracellular PDI with a function-blocking antibody prolongs tail
bleeding times in mice, raising a concern that specific inhibition of PDI may perturb hemostatic function. Our
recent studies have demonstrated that platelet-released PDI promotes the ligand-binding function of glycoprotein
Ibα (GPIbα) and enhances GPIbα-mediated platelet adhesiveness, platelet-neutrophil aggregation and vascular
occlusion under thromboinflammatory conditions. These results suggest that inhibitors blocking the PDI-GPIbα
signaling axis may be a novel antithromboinflammatory drug. Using high throughput screening, we have
identified one compound that specifically inhibits PDI-GPIbα binding and GPIbα-mediated platelet aggregation.
We have found that iv injection of the compound into mice abolishes platelet-neutrophil interactions and improves
blood flow rates in microvessels under thromboinflammatory conditions. Unlike a conventional inhibitor of PDI or
GPIbα, treatment with our compound does not prolong tail bleeding times in mice. These results have provided
evidence for the feasibility of identifying small-molecule inhibitors targeting a specific PDI signaling pathway. In
Aim 1, using the computer-aided drug design technique and a series of in vitro studies, we will identify small-
molecule compounds that specifically block PDI-GPIbα signaling and GPIbα-mediated platelet functions. In Aim
2, we will synthesize derivatives of hits, test them in animal studies and examine DMPK profiles of the selected
compounds. The proposed study will prove that compared to conventional inhibition of PDI or GPIbα, specific
inhibition of the PDI-GPIbα signaling axis might be a safer and effective therapeutic strategy for treating
thromboinflammatory disease.

## Key facts

- **NIH application ID:** 10242945
- **Project number:** 5R33HL154107-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jaehyung Cho
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $551,250
- **Award type:** 5
- **Project period:** 2020-09-04 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242945

## Citation

> US National Institutes of Health, RePORTER application 10242945, Identification of an inhibitor of PDI-GPIbalpha signaling as a novel antithromboinflammatory agent (5R33HL154107-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242945. Licensed CC0.

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