Publication

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

Journal Paper/Review - Nov 15, 2007

Units
PubMed
Doi

Citation
Burster T, Kalbacher H, Verhelst S, Weber E, Falk K, Rotzschke O, Dunn S, Boehm B, Marin-Esteban V, Driessen C. Design of protease-resistant myelin basic protein-derived peptides by cleavage site directed amino acid substitutions. Biochemical pharmacology 2007; 74:1514-23.
Type
Journal Paper/Review (English)
Journal
Biochemical pharmacology 2007; 74
Publication Date
Nov 15, 2007
Issn Print
0006-2952
Pages
1514-23
Brief description/objective

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.