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Article Dans Une Revue Applied Sciences Année : 2022

In-Silico Characterization of von Willebrand Factor Bound to FVIII

Résumé

Factor VIII belongs to the coagulation cascade and is expressed as a long pre-protein (mature form, 2351 amino acids long). FVIII is deficient or defective in hemophilic A patients, who need to be treated with hemoderivatives or recombinant FVIII substitutes, i.e., biologic drugs. The interaction between FVIII and von Willebrand factor (VWF) influences the pharmacokinetics of FVIII medications. In vivo, full-length FVIII (FL-FVIII) is secreted in a plasma-inactive form, which includes the B domain, which is then proteolyzed by thrombin protease activity, leading to an inactive plasma intermediate. In this work, we analyzed through a computational approach the binding of VWF with two structure models of FVIII (secreted full-length with B domain, and B domain-deleted FVIII). We included in our analysis the atomic model of efanesoctocog alfa, a novel and investigational recombinant FVIII medication, in which the VWF is covalently linked to FVIII. We carried out a structural analysis of VWF/FVIII interfaces by means of protein–protein docking, PISA (Proteins, Interfaces, Structures and Assemblies), and protein contact networks (PCN) analyses. Accordingly, our computational approaches to previously published experimental data demonstrated that the domains A3-C1 of B domain-deleted FVIII (BDD-FVIII) is the preferential binding site for VWF. Overall, our computational approach applied to topological analysis of protein–protein interface can be aimed at the rational design of biologic drugs other than FVIII medications.
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Dates et versions

hal-03814955 , version 1 (18-10-2022)

Identifiants

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Valentina Drago, Luisa Di Paola, Claire Lesieur, Renato Bernardini, Claudio Bucolo, et al.. In-Silico Characterization of von Willebrand Factor Bound to FVIII. Applied Sciences, 2022, 12 (15), pp.7855. ⟨10.3390/app12157855⟩. ⟨hal-03814955⟩
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