| Abstract
| - The immunodominant myelin basic protein (MBP) peptide comprising residues 87−99 is a self-antigen in multiple sclerosis (MS). In Lewis rats this epitope induces experimental allergicencephalomyelitis (EAE), a demyelinating disease of the central nervous system, and is a modelof MS. Structure−activity studies have shown that Lys91 and Pro96 residues are important forencephalitogenicity. Replacement of Lys and/or Pro residues with Arg and/or Ala, respectively,results in suppression of EAE. A potent linear altered peptide ligand of the immunodominantsequence MBP83-99 has been selected for clinical trial (Nat. Med. 2000, 6, 1167, 1176). In thepresent report, two cyclic analogues, cyclo(91−99)[Ala96]MBP87-99 and cyclo(87−99)[Arg91,Ala96]MBP87-99 were designed by NMR and molecular modeling data on human MBP87-99 epitope(Val87-His-Phe-Phe-Lys-Asn-Ile-Val-Thr-Pro-Arg-Thr-Pro99) and its linear antagonist peptideanalogue [Arg91, Ala96]MBP87-99. These analogues (altered peptide ligands) inhibited EAE inLewis rats and decreased inflammation in the spinal cord. In addition, the analogue cyclo(87−99)[Arg91, Ala96]MBP87-99 induced proliferation of human peripheral blood T-cells. Thesecyclic MBP87-99 peptide analogues may lead to the design of potent antagonist mimetics fortreating MS.
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