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Updated: Jun 22, 2025
12:24
Helical Organization of Blood Coagulation Factor VIII on Lipid Nanotubes
Published on: June 3, 2014
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Binding Promiscuity of Therapeutic Factor VIII
Alejandra Reyes Ruiz1, Aishwarya S Bhale2, Krishnan Venkataraman2
1Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, CNRS, Sorbonne Université, Université Paris Cité, Paris, France.
Thrombosis and Haemostasis
|July 1, 2024
Summary
Protein binding promiscuity can cause issues with drug efficacy and safety. This review explores factor VIII (FVIII) binding promiscuity, suggesting strategies to improve protein drug development.
Area of Science:
- Biochemistry
- Pharmacology
- Protein Engineering
Background:
- Binding promiscuity in proteins can lead to adverse effects in protein-based drugs, including off-target reactivity and immunogenicity.
- Factor VIII (FVIII) is a critical protein therapeutic for hemophilia A but exhibits poor pharmacokinetics and high immunogenicity, potentially linked to binding promiscuity.
Purpose of the Study:
- To review the evidence for binding promiscuity in factor VIII (FVIII).
- To identify molecular interactions contributing to FVIII's therapeutic liabilities.
- To propose strategies for predicting and mitigating protein binding promiscuity in drug development.
Main Methods:
- Literature review of existing studies on factor VIII (FVIII) interactions and properties.
- Analysis of canonical and noncanonical binding events of FVIII in circulation.
- Examination of the role of specific FVIII domains in binding promiscuity.
Main Results:
- Factor VIII (FVIII) displays binding promiscuity, contributing to its clinical limitations.
- Both canonical and noncanonical interactions are implicated in FVIII's therapeutic liabilities.
- The FVIII light chain, particularly the C1 and C2 domains, appears crucial for binding promiscuity.
Conclusions:
- Understanding FVIII binding promiscuity offers insights into protein drug development.
- Strategies can be developed to predict and reduce binding promiscuity, enhancing drug efficacy and safety.
- Targeting FVIII's binding promiscuity can guide the design of improved protein therapeutics.
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