Design of Novel Cyclic Altered Peptide Ligands of Myelin Basic Protein MBP83−99 That Modulate Immune Responses in SJL/J Mice

• Published in: Journal of medicinal chemistry Vol. 51; no. 13; pp. 3971 - 3978
• Main Authors: Katsara, Maria, Deraos, George, Tselios, Theodore, Matsoukas, John, Apostolopoulos, Vasso
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 10.07.2008
• Subjects: Amino Acid Sequence; Animals; Antibody Formation - immunology; Biological and medical sciences; Cell Proliferation - drug effects; Cells, Cultured; Cyclization; Drug Design; Female; Immunomodulators; Immunosuppressive Agents - chemistry; Immunosuppressive Agents - pharmacology; Interferon-gamma - metabolism; Interleukin-4 - biosynthesis; Ligands; Medical sciences; Mice; Molecular Sequence Data; Mutation - genetics; Myelin Basic Protein - chemistry; Myelin Basic Protein - genetics; Myelin Basic Protein - metabolism; Peptide Fragments - chemistry; Peptide Fragments - genetics; Peptide Fragments - pharmacology; Peptides, Cyclic - chemistry; Peptides, Cyclic - genetics; Peptides, Cyclic - pharmacology; Pharmacology. Drug treatments; T-Lymphocytes - cytology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Multiple sclerosis; Immune response; Myelin; Cyclic peptides; Rodentia; Cytokine; Splenocyte; Immunomodulator; Vertebrata; Interleukin 4; Mammalia; Treatment; Structure activity relation; Mouse; Basic protein; Animal; Peptide synthesis; Inhibition; Solid phase; Chemical synthesis; Gamma interferon
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm8000554

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 MBP83−99 epitope. A number of cyclic analogues were tested for their ability to inhibit (antagonize) Th1 (IFN-γ) responses, and cyclo(83−99)[A91]MBP83−99 mutant peptide was found to be the most efficient inhibitor. We demonstrated that cyclo(83−99)[A91]MBP83−99 peptide emulsified in CFA enhanced Th2 (IL-4) and antibody responses in vivo. Moreover, immunization of mice with antagonist cyclo(83−99)[A91]MBP83−99 peptide conjugated to reduced mannan enhanced IL-4 responses compared to cyclo(83−99)MBP83−99 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)[A91]MBP83−99 is a promising mutant peptide analogue for the potential treatment of MS.