title: Design of protease-resistant myelin basic protein-derived peptides by cleavage site directed amino acid substitutions.
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.
authors.affiliation: Department of Medicine II, University of Tübingen, Tübingen, Germany. tburster@stanford.edu
authors.forename: Timo
authors.initials: T
authors.lastname: Burster
authors.forename: Viviana
authors.initials: V
authors.lastname: Marin-Esteban
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Boehm
authors.forename: Shannon
authors.initials: S
authors.lastname: Dunn
authors.forename: Olaf
authors.initials: O
authors.lastname: Rotzschke
authors.forename: Kirsten
authors.initials: K
authors.lastname: Falk
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Weber
authors.forename: Steven H L
authors.initials: SH
authors.lastname: Verhelst
authors.forename: Hubert
authors.initials: H
authors.lastname: Kalbacher
authors.forename: Christoph
authors.initials: C
authors.lastname: Driessen
mesh_terms: 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