دورية
Galloylated Polyphenols Represent a New Class of Antithrombotic Antagonists of Thiol Isomerases
| العنوان: | Galloylated Polyphenols Represent a New Class of Antithrombotic Antagonists of Thiol Isomerases |
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| المؤلفون: | Yang, Moua, Kennedy, Quinn, Patel, Anika, Chen, Da-Yuan, Scartelli, Christina, Osataphan, Soravis, Bekendam, Roelof, Xie, Huanzhang, Lin, Lin, Schmaier, Alec A, Saeed, Mohsan, Flaumenhaft, Robert |
| المصدر: | Blood; November 2023, Vol. 142 Issue: 1, Number 1 Supplement 1 p684-684, 1p |
| مستخلص: | Protein disulfide isomerase (PDI) family thiol isomerases are multidomain oxidoreductases that function in thrombus formation. PDI antagonism or targeted genetic deletion blocks thrombus formation in several murine models of thrombosis. PDI has a domain structure of a-b-b'-a'in which the aand a'domains contain the Cys-Gly-His-Cys catalytic motifs responsible for disulfide shuffling and the band b'domains are the substrate binding domains. We have previously identified flavonoid quercetins and bepristats as two structure independent classes of PDI inhibitors that act by binding the hydrophobic pocket in the b'domain and eliciting allosteric modifications that impair oxidoreductase activity. While screening a flavonoid library for inhibitors of the SARS-CoV-2 main protease (Mpro), we identified a Mpro inhibitor termed PGHG that blocked PDI reductase activity with an IC 50of 1.5+0.6 µM. When tested against isolated domains of PDI, PGHG inhibited aand a'fragments as well as ab, b'xa'and abb'xfragments, indicating that it acts on the aand a'domains of PDI. Supportive of an activity at the aand/or a'domains, PGHG inhibited other vascular thiol isomerases including ERp5, ERp46, ERp57, and ERp72 with IC 50s of 1.5, 3.9, 3.3, and 7.8 µM, respectively. When tested in a cremaster muscle murine model of thrombus formation, PGHG (25 mg/kg) inhibited platelet accumulation to 18+6% of control levels and fibrin formation to 21+3% of controls (Fig. 1). In contrast, when tested in the mice tail transection model of bleeding, PGHG did not prolong the time to cessation of bleeding nor the total amount of blood loss. These results show that PGHG can inhibit thrombus formation without promoting bleeding. |
| قاعدة البيانات: | Supplemental Index |
| تدمد: | 00064971 15280020 |
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| DOI: | 10.1182/blood-2023-190367 |