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Article

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

Supporting Info

Maria Katsara^†^§, George Deraos^§, Theodore Tselios^§, John Matsoukas^§, Vasso Apostolopoulos*^†

Immunology and Vaccine Laboratory, Burnet Institute (Austin Campus), Studley Road, Heidelberg, 3084 Victoria, Australia, and Department of Chemistry, Section of Organic Chemistry, Biochemistry, and Natural Products, University of Patras, 26500 Patras, Greece

J. Med. Chem., 2008, 51 (13), pp 3971–3978

DOI: 10.1021/jm8000554

Publication Date (Web): June 19, 2008

†

Burnet Institute (Austin Campus).

University of Patras.

* To whom correspondence should be addressed. Phone: +61-3-92870666. Fax: +61-3-92870600. E-mail: vasso@burnet.edu.au.

Abstract

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.

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