Design of protease-resistant myelin basic protein-derived peptides by cleavage site directed amino acid substitutions

Timo Burster, Viviana Marin-Esteban, Bernhard O Boehm, Shannon Dunn, Olaf Rotzschke, Kirsten Falk, Ekkehard Weber, Steven H L Verhelst, Hubert Kalbacher, Christoph Driessen

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8 Citations (Scopus)

Abstract

Multiple Sclerosis (MS) is considered to be a T cell-mediated autoimmune disease. An attractive strategy to prevent activation of autoaggressive T cells in MS, is the use of altered peptide ligands (APL), which bind to major histocompatibility complex class II (MHC II) molecules. To be of clinical use, APL must be capable of resisting hostile environments including the proteolytic machinery of antigen presenting cells (APC). The current design of APL relies on cost- and labour-intensive strategies. To overcome these major drawbacks, we used a deductive approach which involved modifying proteolytic cleavage sites in APL. Cleavage site-directed amino acid substitution of the autoantigen myelin basic protein (MBP) resulted in lysosomal protease-resistant, high-affinity binding peptides. In addition, these peptides mitigated T cell activation in a similar fashion as conventional APL. The strategy outlined allows the development of protease-resistant APL and provides a universal design strategy to improve peptide-based immunotherapeutics.

Original languageEnglish
Pages (from-to)1514-23
Number of pages10
JournalBiochemical Pharmacology
Volume74
Issue number10
DOIs
Publication statusPublished - Nov 15 2007
Externally publishedYes

Keywords

  • Amino Acid Substitution
  • Cathepsins
  • Cell Line
  • Cell Proliferation
  • HLA-DR Antigens
  • HLA-DRB1 Chains
  • Humans
  • Interleukin-2
  • Lysosomes
  • Myelin Basic Protein
  • Peptides
  • T-Lymphocytes
  • Journal Article
  • Research Support, Non-U.S. Gov't

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    Burster, T., Marin-Esteban, V., Boehm, B. O., Dunn, S., Rotzschke, O., Falk, K., Weber, E., Verhelst, S. H. L., Kalbacher, H., & Driessen, C. (2007). Design of protease-resistant myelin basic protein-derived peptides by cleavage site directed amino acid substitutions. Biochemical Pharmacology, 74(10), 1514-23. https://doi.org/10.1016/j.bcp.2007.07.037