Antagonistic Effects of Human Cyclic MBP_87-99Altered Peptide Ligands in Experimental Allergic Encephalomyelitis and Human T-Cell Proliferation

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 allergic encephalomyelitis (EAE), a demyelinating disease of the central nervous system, and is a model of MS. Structure−activity studies have shown that Lys91 and Pro96 residues are important for encephalitogenicity. 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 immunodominant sequence MBP83-99 has been selected for clinical trial (Nat. Med. 2000, 6, 1167, 1176). In the present 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 peptide analogue [Arg91, Ala96]MBP87-99. These analogues (altered peptide ligands) inhibited EAE in Lewis 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. These cyclic MBP87-99 peptide analogues may lead to the design of potent antagonist mimetics for treating MS.