Design of novel cyclic altered peptide ligands of myelin basic protein MBP83-99 that modulate immune responses in SJL/J mice.
The use of antagonist peptides derived from the myelin sheath constitutes a promising therapeutic approach for multiple sclerosis (MS). Cyclization of peptide analogues is of great interest, since the limited stability of linear peptides restricts their potential as therapeutic agents. Herein, we designed and synthesized a number of cyclic peptides by mutating TCR contact sites of the MBP 83-99 epitope. A number of cyclic analogues were tested for their ability to inhibit (antagonize) Th1 (IFN-gamma) responses, and cyclo(83-99)[A (91)]MBP 83-99 mutant peptide was found to be the most efficient inhibitor. We demonstrated that cyclo(83-99)[A (91)]MBP 83-99 peptide emulsified in CFA enhanced Th2 (IL-4) and antibody responses in vivo. Moreover, immunization of mice with antagonist cyclo(83-99)[A (91)]MBP 83-99 peptide conjugated to reduced mannan enhanced IL-4 responses compared to cyclo(83-99)MBP 83-99 peptide. Thus, cyclized peptides, which offer greater stability and enhanced responses, are novel leads for the immunotherapy of many diseases, such as MS. In particular, cyclo(83-99)[A (91)]MBP 83-99 is a promising mutant peptide analogue for the potential treatment of MS.
Katsara
Maria
M
Immunology and Vaccine Laboratory, Burnet Institute (Austin Campus), Studley Road, Heidelberg, 3084 Victoria, Australia.
Deraos
George
G
Tselios
Theodore
T
Matsoukas
John
J
Apostolopoulos
Vasso
V
D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003500:Cyclization; D015195:Drug Design; D005260:Female; D007166:Immunosuppressive Agents / Q000737:chemistry* / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000096:biosynthesis; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D004676:Myelin Basic Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D007166:Immunosuppressive Agents; D008024:Ligands; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D015847:Interleukin-4; D007371:Interferon-gamma