title: Treatment of experimental allergic encephalomyelitis (EAE) induced by guinea pig myelin basic protein epitope 72-85 with a human MBP(87-99) analogue and effects of cyclic peptides.
abstract: Experimental autoimmune encephalomyelitis (EAE) is an inflammatory and demyelinating disease of the central nervous system and is an animal model of multiple sclerosis (MS). In the present report, a linear analogue and a series of cyclic semi-mimetic peptides were designed and synthesized based on the human myelin basic protein (MBP(87-99)) epitope (Val87-His-Phe-Phe-Lys-Asn-Ile-Val-Thr-Pro-Arg-Thr-Pro90) and on Copolymer I (a mixture of random polymers of Ala, Gln, Lys and Tyr used to treat MS). These analogues were designed looking for suppressors of EAE induced by guinea pig MBP(72-85) epitope (Gln-Lys-Ser-Gln-Arg-Ser-Gln-Asp-Glu-Asn-Pro-Val) in Lewis rats. The linear analogue [Arg91,Ala96]MBP(87-99), in which Arg substitutes Lys91 and Ala substitutes Pro96, was found to be a strong inhibitor which when administered to Lewis rats together with the encephalitogenic agonist MBP(72-85) completely prevented the induction of EAE. In contrast, three N- and C-termini amide-linked cyclic semi-mimetic peptides, [cyclo-Phe-Arg-Asn-Ile-Val-Thr-Ala-Acp (1), cyclo-Phe-Ala-Arg-Gln-Acp (2), cyclo-Tyr-Ala-Lys-Gln-Acp (3)] as well as a Lys side chain and C-terminous cyclic semi mimetic peptide cyclo(Lys, Acp)-Phe-Lys-Asn-Ile-Val-Thr-Ala-Acp (4) which contain segments of MBP(87-99) or are constituted from immunophoric residues of copolymer 1, were ineffective in inducing or inhibiting EAE in Lewis rats. However co-injection of cyclic analogues with MBP(72-85) delayed the onset of EAE indicating a modulatory effect on the EAE activity of MBP(72-85). These findings suggest that molecule length, size of cyclic moiety and backbone conformation are important elements for immunogenic activity. Moreover blockade of MBP(72-85) induced EAE by the unrelated peptide [Arg91,Ala56]MBP(87-99) could indicate that the mechanism of inhibition is not due to binding competition but rather due to the delivery of a negative signal by the antagonist which overcomes the agonist response possibly through the activation of antigen specific regulatory T cells.
authors.affiliation: Department of Chemistry, University of Patras, Greece.
authors.forename: T
authors.initials: T
authors.lastname: Tselios
authors.forename: I
authors.initials: I
authors.lastname: Daliani
authors.forename: L
authors.initials: L
authors.lastname: Probert
authors.forename: S
authors.initials: S
authors.lastname: Deraos
authors.forename: E
authors.initials: E
authors.lastname: Matsoukas
authors.forename: S
authors.initials: S
authors.lastname: Roy
authors.forename: J
authors.initials: J
authors.lastname: Pires
authors.forename: G
authors.initials: G
authors.lastname: Moore
authors.forename: J
authors.initials: J
authors.lastname: Matsoukas
mesh_terms: D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D004676:Myelin Basic Protein / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew
chemical_list: D004676:Myelin Basic Protein; D010446:Peptide Fragments; D010456:Peptides, Cyclic; C118872:myelin basic protein 72-85; C115314:myelin basic protein 87-99