{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T01:22:10Z","timestamp":1792027330084,"version":"4.4.0"},"reference-count":55,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,2,12]],"date-time":"2022-02-12T00:00:00Z","timestamp":1644624000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"publisher","award":["675746"],"award-info":[{"award-number":["675746"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"publisher","award":["766118"],"award-info":[{"award-number":["766118"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The plasmatic von Willebrand factor (VWF) circulates in a compact form unable to bind platelets. Upon shear stress, the VWF A1 domain is exposed, allowing VWF-binding to platelet glycoprotein Ib-V-IX (GPIb\u03b1 chain). For a better understanding of the role of this interaction in cardiovascular disease, molecules are needed to specifically interfere with the opened VWF A1 domain interaction with GPIb\u03b1. Therefore, we in silico designed and chemically synthetized stable cyclic peptides interfering with the platelet-binding of the VWF A1 domain per se or complexed with botrocetin. Selected peptides (26\u201334 amino acids) with the lowest-binding free energy were: the monocyclic mono- vOn Willebrand factoR-GPIb\u03b1 InTerference (ORbIT) peptide and bicyclic bi-ORbIT peptide. Interference of the peptides in the binding of VWF to GPIb-V-IX interaction was retained by flow cytometry in comparison with the blocking of anti-VWF A1 domain antibody CLB-RAg35. In collagen and VWF-dependent whole-blood thrombus formation at a high shear rate, CLB-RAg35 suppressed stable platelet adhesion as well as the formation of multilayered thrombi. Both peptides phenotypically mimicked these changes, although they were less potent than CLB-RAg35. The second-round generation of an improved peptide, namely opt-mono-ORbIT (28 amino acids), showed an increased inhibitory activity under flow. Accordingly, our structure-based design of peptides resulted in physiologically effective peptide-based inhibitors, even for convoluted complexes such as GPIb\u03b1-VWF A1.<\/jats:p>","DOI":"10.3390\/ijms23042046","type":"journal-article","created":{"date-parts":[[2022,2,13]],"date-time":"2022-02-13T21:08:43Z","timestamp":1644786523000},"page":"2046","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Structure-Based Cyclic Glycoprotein Ib\u03b1-Derived Peptides Interfering with von Willebrand Factor-Binding, Affecting Platelet Aggregation under Shear"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6095-8972","authenticated-orcid":false,"given":"Johana","family":"Hrdinova","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6200 MD Maastricht, The Netherlands"},{"name":"Department of Molecular and Cellular Hemostasis, Sanquin-Academic Medical Center, 1011 LZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5055-9019","authenticated-orcid":false,"given":"Delia I.","family":"Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6200 MD Maastricht, The Netherlands"},{"name":"Platelet Proteomics Group, Center for Research in Molecule Medicine and Chronic Diseases (CiMUS), Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bogac","family":"Ercig","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6200 MD Maastricht, The Netherlands"},{"name":"Department of Molecular and Cellular Hemostasis, Sanquin-Academic Medical Center, 1011 LZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bibian M. E.","family":"Tullemans","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis P. L.","family":"Suylen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5973-272X","authenticated-orcid":false,"given":"Stijn M.","family":"Agten","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5313-4035","authenticated-orcid":false,"given":"Kerstin","family":"Jurk","sequence":"additional","affiliation":[{"name":"Center for Thrombosis and Hemostasis (CTH), University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0142-0843","authenticated-orcid":false,"given":"Tilman M.","family":"Hackeng","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Vanhoorelbeke","sequence":"additional","affiliation":[{"name":"Laboratory for Thrombosis Research, Interdisciplinary Research Facility Life Sciences, Katholieke Universiteit Leuven Campus Kulak Kortrijk, 8500 Kortrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Voorberg","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Hemostasis, Sanquin-Academic Medical Center, 1011 LZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2334-9403","authenticated-orcid":false,"given":"Chris P. M.","family":"Reutelingsperger","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9678-7084","authenticated-orcid":false,"given":"Kanin","family":"Wichapong","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2848-5121","authenticated-orcid":false,"given":"Johan W. M.","family":"Heemskerk","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6200 MD Maastricht, The Netherlands"},{"name":"Synapse Research Institute, Kon. Emmaplein 7, 6214 AC Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerry A. F.","family":"Nicolaes","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1146\/annurev.biochem.67.1.395","article-title":"Biochemistry and genetics of von Willebrand factor","volume":"67","author":"Sadler","year":"1998","journal-title":"Annu. Rev. Biochem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1146\/annurev.cb.06.110190.001245","article-title":"Cell biology of von Willebrand factor","volume":"6","author":"Wagner","year":"1990","journal-title":"Annu. Rev. 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