Design of novel cyclic altered peptide ligands of myelin basic protein MBP(83-99) 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 de...
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Published in | Journal of medicinal chemistry Vol. 51; no. 13; pp. 3971 - 3978 |
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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 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. |
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AbstractList | 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. |
Author | Matsoukas, John Apostolopoulos, Vasso Tselios, Theodore Katsara, Maria Deraos, George |
Author_xml | – sequence: 1 givenname: Maria surname: Katsara fullname: Katsara, Maria organization: Burnet Inst, Immunol & Vaccine Lab, Heidelberg, Vic 3084, Australia – sequence: 2 givenname: George surname: Deraos fullname: Deraos, George organization: Univ Patras, Dept Chem, Sect Organ Chem Biochem & Nat Prod, Patras 26500, Greece – sequence: 3 givenname: Theodore surname: Tselios fullname: Tselios, Theodore organization: Univ Patras, Dept Chem, Sect Organ Chem Biochem & Nat Prod, Patras 26500, Greece – sequence: 4 givenname: John surname: Matsoukas fullname: Matsoukas, John organization: Univ Patras, Dept Chem, Sect Organ Chem Biochem & Nat Prod, Patras 26500, Greece – sequence: 5 givenname: Vasso orcidid: 0000-0001-6788-2771 surname: Apostolopoulos fullname: Apostolopoulos, Vasso email: vasso@burnet.edu.au organization: Burnet Inst, Immunol & Vaccine Lab, Heidelberg, Vic 3084, Australia |
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Keywords | MULTIPLE-SCLEROSIS PATIENTS EPITOPE ANALOG RECOGNITION AMINO-ACIDS EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS INDUCTION MANNAN T-CELLS ANTIGEN |
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Title | Design of novel cyclic altered peptide ligands of myelin basic protein MBP(83-99) that modulate immune responses in SJL/J mice |
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