TY - JOUR
T1 - Structure-Based Cyclic Glycoprotein Ibα-Derived Peptides Interfering with von Willebrand Factor-Binding, Affecting Platelet Aggregation under Shear
AU - Hrdinova, Johana
AU - Fernández, Delia I.
AU - Ercig, Bogac
AU - Tullemans, Bibian M. E.
AU - Suylen, Dennis P. L.
AU - Agten, Stijn M.
AU - Jurk, Kerstin
AU - Hackeng, Tilman M.
AU - Vanhoorelbeke, Karen
AU - Voorberg, Jan
AU - Reutelingsperger, Chris P. M.
AU - Wichapong, Kanin
AU - Heemskerk, Johan W. M.
AU - Nicolaes, Gerry A. F.
N1 - Funding Information: This work was supported by the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska–Curie grant agreements No. 675746 (PROFILE) to JH and BE, and No. 766118 (TAPAS) to DIF. DIF is enrolled in a joint PhD program of the University of Maastricht (NL) and Santiago da Compostela (ES). Funding Information: Funding: This work was supported by the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska–Curie grant agreements No. 675746 (PROFILE) to JH and BE, and No. 766118 (TAPAS) to DIF. DIF is enrolled in a joint PhD program of the University of Maastricht (NL) and Santiago da Compostela (ES). Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/2/1
Y1 - 2022/2/1
N2 - 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 CLBRAg35. 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.
AB - 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 CLBRAg35. 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.
KW - Glycoprotein Ib
KW - In silico peptide design
KW - Platelets
KW - Thrombus
KW - Von Willebrand factor
UR - http://www.scopus.com/inward/record.url?scp=85124373796&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/ijms23042046
DO - https://doi.org/10.3390/ijms23042046
M3 - Article
C2 - 35216161
SN - 1661-6596
VL - 23
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 4
M1 - 2046
ER -