Design of protease-resistant myelin basic protein-derived peptides by cleavage site directed amino acid substitutions.
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.
Burster
Timo
T
Department of Medicine II, University of Tübingen, Tübingen, Germany. tburster@stanford.edu
Marin-Esteban
Viviana
V
Boehm
Bernhard O
BO
Dunn
Shannon
S
Rotzschke
Olaf
O
Falk
Kirsten
K
Weber
Ekkehard
E
Verhelst
Steven H L
SH
Kalbacher
Hubert
H
Driessen
Christoph
C
D019943:Amino Acid Substitution; D002403:Cathepsins / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D006684:HLA-DR Antigens / Q000378:metabolism; D059811:HLA-DRB1 Chains; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D004676:Myelin Basic Protein / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism