Design and Evaluation of Novel Peptides Targeting Protein Disulfide Isomerase as Antiplatelet Agents
6 affiliations
- 1Thrombosis and Healthy Aging Research Center, Department of Clinical Biochemistry and Immunohematology, Faculty of Health Sciences, University of Talca, Talca 3460000, Chile
- 2Margarita Salas Biological Research Centre, Spanish National Research Council (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain
- 3Instituto de Ciencia de Materiales de Madrid, Spanish National Research Council (CSIC), C. Sor Juana Inés de la Cruz 3, 28049 Madrid, Spain
- 4Núcleo Biotecnología Curauma, Pontificia Universidad Católica de Valparaíso, Valparaíso 2373223, Chile
- 5Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay
- 6Centro de Estudios en Alimentos Procesados (CEAP), Av. Lircay s/n, Talca 3480094, Chile
Abstract
Extracellular protein disulfide isomerase (PDI) is a critical mediator of thrombus formation and a promising target for novel antithrombotic therapies aiming to overcome the bleeding risks associated with current antiplatelet agents. 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.
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BibTeX
@article{rodriguezcabello2026design,
title = {{Design and Evaluation of Novel Peptides Targeting Protein Disulfide Isomerase as Antiplatelet Agents}},
author = {Francisca Rodríguez-Cabello and Diego Méndez and Eugenia Ulzurrun and Abigail E. Teitgen and Felipe Lagos and Fanny Guzmán and Andrés Trostchansky and Basilio Carrasco and Nuria E. Campillo and Iván Palomo and Eduardo Fuentes},
journal = {Molecules (Basel, Switzerland)},
year = {2026},
month = oct,
doi = {10.3390/molecules31193516},
url = {https://europepmc.org/article/PMC/PMC13666787},
note = {CC BY},
}
RIS
TY - JOUR
TI - Design and Evaluation of Novel Peptides Targeting Protein Disulfide Isomerase as Antiplatelet Agents
AU - Francisca Rodríguez-Cabello
AU - Diego Méndez
AU - Eugenia Ulzurrun
AU - Abigail E. Teitgen
AU - Felipe Lagos
AU - Fanny Guzmán
AU - Andrés Trostchansky
AU - Basilio Carrasco
AU - Nuria E. Campillo
AU - Iván Palomo
AU - Eduardo Fuentes
PY - 2026
DA - 2026/10/01
JO - Molecules (Basel, Switzerland)
DO - 10.3390/molecules31193516
UR - https://europepmc.org/article/PMC/PMC13666787
AB - Extracellular protein disulfide isomerase (PDI) is a critical mediator of thrombus formation and a promising target for novel antithrombotic therapies aiming to overcome the bleeding risks associated with current antiplatelet agents. 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.
SN - 1420-3049
ER -