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This study aimed to design and evaluate novel, targeted peptide-based PDI inhibitors with a safe physiological profile. We utilized a bioinformatics-driven rational design approach, based on the evolutionary conservation of the PDI active site, to generate a library of 34 targeted peptides. The inhibitory mechanism and biological efficacy of the lead candidate, peptide p23, were evaluated using 500 ns molecular dynamics (MD) simulations, flow cytometry, and in vitro microfluidic thrombosis models under arterial shear stress. Based on bioinformatic analyses, p23 is predicted to interact with the PDI catalytic cleft and potentially form a highly stable inhibitory complex. Functionally, p23 maintained consistent antiplatelet efficacy in the complex matrix of human platelet-rich plasma. Flow cytometry demonstrated that p23 selectively suppresses integrin GPIIb\/IIIa conformational activation without impairing P-selectin and CD63 surface expression. Crucially, p23 significantly reduced collagen-dependent three-dimensional thrombus formation in whole blood under biomimetic arterial flow, while still allowing for necessary residual platelet adhesion. Unlike direct integrin antagonists, p23 preserved physiological clot retraction and did not prolong plasma coagulation parameters. These findings validate the rational design of covalent PDI inhibitors and highlight peptide p23 as a promising candidate for preclinical in vivo evaluation, offering a favorable preliminary hemostatic profile and the potential for a reduced impact on hemostasis.<\/jats:p>","DOI":"10.3390\/molecules31193516","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T08:15:18Z","timestamp":1790928918000},"page":"3516","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design and Evaluation of Novel Peptides Targeting Protein Disulfide Isomerase as Antiplatelet Agents"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7565-8419","authenticated-orcid":false,"given":"Francisca","family":"Rodr\u00edguez-Cabello","sequence":"first","affiliation":[{"name":"Thrombosis and Healthy Aging Research Center, Department of Clinical Biochemistry and Immunohematology, Faculty of Health Sciences, University of Talca, Talca 3460000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0156-2913","authenticated-orcid":false,"given":"Diego","family":"M\u00e9ndez","sequence":"additional","affiliation":[{"name":"Thrombosis and Healthy Aging Research Center, Department of Clinical Biochemistry and Immunohematology, Faculty of Health Sciences, University of Talca, Talca 3460000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7665-2167","authenticated-orcid":false,"given":"Eugenia","family":"Ulzurrun","sequence":"additional","affiliation":[{"name":"Margarita Salas Biological Research Centre, Spanish National Research Council (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5134-7261","authenticated-orcid":false,"given":"Abigail E.","family":"Teitgen","sequence":"additional","affiliation":[{"name":"Margarita Salas Biological Research Centre, Spanish National Research Council (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain"},{"name":"Instituto de Ciencia de Materiales de Madrid, Spanish National Research Council (CSIC), C. Sor Juana In\u00e9s de la Cruz 3, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe","family":"Lagos","sequence":"additional","affiliation":[{"name":"Thrombosis and Healthy Aging Research Center, Department of Clinical Biochemistry and Immunohematology, Faculty of Health Sciences, University of Talca, Talca 3460000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7829-0568","authenticated-orcid":false,"given":"Fanny","family":"Guzm\u00e1n","sequence":"additional","affiliation":[{"name":"N\u00facleo Biotecnolog\u00eda Curauma, Pontificia Universidad Cat\u00f3lica de Valpara\u00edso, Valpara\u00edso 2373223, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9721-7577","authenticated-orcid":false,"given":"Andr\u00e9s","family":"Trostchansky","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica and Centro de Investigaciones Biom\u00e9dicas (CEINBIO), Facultad de Medicina, Universidad de la Rep\u00fablica, Montevideo 11800, Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basilio","family":"Carrasco","sequence":"additional","affiliation":[{"name":"Centro de Estudios en Alimentos Procesados (CEAP), Av. 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