{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:58:21Z","timestamp":1785437901043,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,3]]},"group-title":"Biochemistry","reference-count":55,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T00:00:00Z","timestamp":1777766400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"crossref","award":["R00HL164888"],"award-info":[{"award-number":["R00HL164888"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"crossref","award":["R00HL177831"],"award-info":[{"award-number":["R00HL177831"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100016867","name":"Zoll Foundation","doi-asserted-by":"crossref","award":["Award"],"award-info":[{"award-number":["Award"]}],"id":[{"id":"10.13039\/100016867","id-type":"DOI","asserted-by":"crossref"}]},{"award":["Investigator Startup Fund"],"award-info":[{"award-number":["Investigator Startup Fund"]}],"id":[{"id":"https:\/\/ror.org\/00ek9j693","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Punicalagin, an ellagic acid polyphenol from pomegranate, has been proposed as an antagonist of protein disulfide isomerase (PDI) and endoplasmic reticulum resident protein 57 (ERp57), thiol oxidoreductases that regulate protein folding and extracellular thrombotic signaling. Here, biochemical oxidase and reductase assays on PDI show that punicalagin inhibits both activities with micromolar potency, thereby extending earlier work that described only disulfide reductase inhibition. In parallel, thiol labeling of catalytic cysteines revealed no change in the redox state, supporting a noncovalent, allosteric of inhibition. Molecular docking and molecular dynamics simulations showed that punicalagin binds stably and preferentially to defined sites on the N\u2370terminal domains of PDI through extensive hydrogen bonding and van der Waals contacts, which is an alternative binding mode to previously reported C-terminal binding. Finally, artificial intelligence-driven network analysis identified PDI as a high-confidence target of punicalagin and related galloylated polyphenols, alongside additional signaling proteins. Together, these findings provide further mechanistic framework for punicalagin-mediated antagonism of PDI and highlight galloylated polyphenols as promising scaffolds for protein disulfide isomerase-targeted therapeutics.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Punicalagin, a galloylated polyphenol, antagonizes not only the reductase activity but also the oxidase activity of protein disulfide isomerase<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Protein disulfide isomerase inhibition by punicalagin is through N-terminal binding<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Punicalagin inhibits conformationally rather than catalytic cysteine modification<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Artificial intelligence network analysis reveals pathway inhibition by punicalagin<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.29.721714","type":"posted-content","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T08:30:13Z","timestamp":1777883413000},"source":"Crossref","is-referenced-by-count":0,"title":["Molecular insights into protein disulfide isomerase antagonism by punicalagin"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-2320-9863","authenticated-orcid":false,"given":"Osamede C.","family":"Owegie","sequence":"first","affiliation":[{"name":"Bloodworks Northwest Research Institute, Seattle, WA 98102, 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