Structure-Based Cyclic Glycoprotein Ibα-Derived Peptides Interfering with von Willebrand Factor-Binding, Affecting Platelet Aggregation under Shear

Autor: Johana Hrdinova, Delia I. Fernández, Bogac Ercig, Bibian M. E. Tullemans, Dennis P. L. Suylen, Stijn M. Agten, Kerstin Jurk, Tilman M. Hackeng, Karen Vanhoorelbeke, Jan Voorberg, Chris P. M. Reutelingsperger, Kanin Wichapong, Johan W. M. Heemskerk, Gerry A. F. Nicolaes
Přispěvatelé: Biochemie, RS: Carim - B02 Vascular aspects thrombosis and Haemostasis, RS: Carim - B03 Cell biochemistry of thrombosis and haemostasis, RS: Carim - B01 Blood proteins & engineering, Experimental Vascular Medicine, Landsteiner Laboratory, ACS - Microcirculation
Rok vydání: 2022
Předmět:
VONWILLEBRAND-FACTOR
Platelet Aggregation
Chemistry
Multidisciplinary
Microfluidics
PROTEIN
von Willebrand factor
ADHESION
Peptides/chemistry
ACTIVATION
DESIGN
DOMAIN
hemic and lymphatic diseases
Cells
Cultured
Spectroscopy
Cultured
General Medicine
in silico peptide design
Computer Science Applications
Chemistry
Platelet Glycoprotein GPIb-IX Complex
thrombus
Physical Sciences
platelets
BOTROCETIN
Blood Platelets/metabolism
Life Sciences & Biomedicine
Protein Binding
glycoprotein Ib
circulatory and respiratory physiology
Blood Platelets
Biochemistry & Molecular Biology
Cells
Platelet Glycoprotein GPIb-IX Complex/chemistry
Stress
von Willebrand Factor/chemistry
Catalysis
Inorganic Chemistry
Animals
Humans
Horses
Physical and Theoretical Chemistry
Molecular Biology
Science & Technology
Binding Sites
COMPLEX
Organic Chemistry
Mechanical
THROMBUS FORMATION
Stress
Mechanical
MONOCLONAL-ANTIBODIES
Peptides
Zdroj: International Journal of Molecular Sciences; Volume 23; Issue 4; Pages: 2046
International journal of molecular sciences, 23(4):2046. Multidisciplinary Digital Publishing Institute (MDPI)
ISSN: 1422-0067
1661-6596
DOI: 10.3390/ijms23042046
Popis: 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. ispartof: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES vol:23 issue:4 ispartof: location:Switzerland status: published
Databáze: OpenAIRE
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