Structure-Based Cyclic Glycoprotein Ibα-Derived Peptides Interfering with von Willebrand Factor-Binding, Affecting Platelet Aggregation under Shear
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 (GPIbα 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 GPIbα. 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 (26-34 amino acids) with the lowest-binding free energy were: the monocyclic mono- vOn Willebrand factoR-GPIbα 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 GPIbα-VWF A1.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:23 |
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| Enthalten in: |
International journal of molecular sciences - 23(2022), 4 vom: 12. Feb. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hrdinova, Johana [VerfasserIn] |
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| Links: |
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| Themen: |
Glycoprotein Ib |
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| Anmerkungen: |
Date Completed 09.03.2022 Date Revised 09.03.2022 published: Electronic Citation Status MEDLINE |
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| doi: |
10.3390/ijms23042046 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM337476632 |
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| 520 | |a 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 (GPIbα 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 GPIbα. 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 (26-34 amino acids) with the lowest-binding free energy were: the monocyclic mono- vOn Willebrand factoR-GPIbα 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 GPIbα-VWF A1 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a glycoprotein Ib | |
| 650 | 4 | |a in silico peptide design | |
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| 650 | 4 | |a thrombus | |
| 650 | 4 | |a von Willebrand factor | |
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| 700 | 1 | |a Fernández, Delia I |e verfasserin |4 aut | |
| 700 | 1 | |a Ercig, Bogac |e verfasserin |4 aut | |
| 700 | 1 | |a Tullemans, Bibian M E |e verfasserin |4 aut | |
| 700 | 1 | |a Suylen, Dennis P L |e verfasserin |4 aut | |
| 700 | 1 | |a Agten, Stijn M |e verfasserin |4 aut | |
| 700 | 1 | |a Jurk, Kerstin |e verfasserin |4 aut | |
| 700 | 1 | |a Hackeng, Tilman M |e verfasserin |4 aut | |
| 700 | 1 | |a Vanhoorelbeke, Karen |e verfasserin |4 aut | |
| 700 | 1 | |a Voorberg, Jan |e verfasserin |4 aut | |
| 700 | 1 | |a Reutelingsperger, Chris P M |e verfasserin |4 aut | |
| 700 | 1 | |a Wichapong, Kanin |e verfasserin |4 aut | |
| 700 | 1 | |a Heemskerk, Johan W M |e verfasserin |4 aut | |
| 700 | 1 | |a Nicolaes, Gerry A F |e verfasserin |4 aut | |
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