More MS news articles for Jan 2002

Antagonistic Effects of Human Cyclic MBP(87-99) Altered Peptide Ligands in Experimental Allergic Encephalomyelitis and Human T-Cell Proliferation

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11784132&dopt=Abstract

J Med Chem 2002 Jan 17;45(2):275-283
Tselios T, Apostolopoulos V, Daliani I, Deraos S, Grdadolnik S, Mavromoustakos T, Melachrinou M, Thymianou S, Probert L, Mouzaki A, Matsoukas J.
Department of Chemistry, University of Patras, 26500 Patras, Greece, Immunology and Vaccine Laboratory, The Austin Research Institute, Heidelberg 3084, Victoria, Australia, Department of Molecular Genetics and Immunology, Hellenic Pasteur Institute, 11521 Athens, Greece, National Hellenic Research Foundation, Institute of Organic and Pharmaceutical Chemistry, 11635 Athens, Greece, National Institute of Chemistry, Hajdrihova 19, P.O. Box 30, SI-1115 Ljubljana, Slovenia, and Laboratory of Pathology and Laboratory Haematology & Transfusion Medicine, Medical School, University of Patras, 26110 Patras, Greece.

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.