Antagonistic effects of human cyclic MBP(87-99) altered peptide ligands in experimental allergic encephalomyelitis and human T-cell proliferation.
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 Lys(91) and Pro(96) 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 MBP(83-99) has been selected for clinical trial (Nat. Med. 2000, 6, 1167, 1176). In the present report, two cyclic analogues, cyclo(91-99)[Ala(96)]MBP(87-99) and cyclo(87-99)[Arg(91), Ala(96)]MBP(87-99) were designed by NMR and molecular modeling data on human MBP(87-99) epitope (Val(87)-His-Phe-Phe-Lys-Asn-Ile-Val-Thr-Pro-Arg-Thr-Pro(99)) and its linear antagonist peptide analogue [Arg(91), Ala(96)]MBP(87-99). These analogues (altered peptide ligands) inhibited EAE in Lewis rats and decreased inflammation in the spinal cord. In addition, the analogue cyclo(87-99)[Arg(91), Ala(96)]MBP(87-99) induced proliferation of human peripheral blood T-cells. These cyclic MBP(87-99) peptide analogues may lead to the design of potent antagonist mimetics for treating MS.
Tselios
Theodore
T
Department of Chemistry, University of Patras, 26500 Patras, Greece.
Apostolopoulos
Vasso
V
Daliani
Ioanna
I
Deraos
Spyros
S
Grdadolnik
Simona
S
Mavromoustakos
Thomas
T
Melachrinou
Maria
M
Thymianou
Sotiria
S
Probert
Lesley
L
Mouzaki
Athanasia
A
Matsoukas
John
J
D000818:Animals; D002455:Cell Division; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000473:pathology; D000939:Epitopes; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D004676:Myelin Basic Protein / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D013116:Spinal Cord / Q000473:pathology; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects*
D000939:Epitopes; D008024:Ligands; D004676:Myelin Basic Protein; D010446:Peptide Fragments; C115314:myelin basic protein 87-99