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Design and synthesis of a novel potent myelin basic protein epitope 87-99 cyclic analogue:  enhanced stability and biological properties of mimics render them a potentially new class of immunomodulators

Matsoukas, John, Apostolopoulos, Vasso, Kalbacher, Hubert, Papini, Anna-Maria, Tselios, Theodore, Chatzantoni, Kokona, Biagioli, Tiziana, Lolli, Francesco, Deraos, Spyros, Papathanassopoulos, Panagiotis, Troganis, Anastassios, Mantzourani, Efthymia D., Mavromoustakos, Thomas and Mouzaki, Athanasia 2005. Design and synthesis of a novel potent myelin basic protein epitope 87-99 cyclic analogue:  enhanced stability and biological properties of mimics render them a potentially new class of immunomodulators. Journal of Medicinal Chemistry 48 (5) , pp. 1470-1480. 10.1021/jm040849g

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Abstract

A cyclic analogue, [cyclo(87−99)MBP87-99], of the human immunodominant MBP87-99 epitope, was designed based on ROESY/NMR distance information and modeling data for linear epitope 87−99, taking into account T-cell (Phe89, Lys91, Pro96) and HLA (His88, Phe90, Ile93) contact side-chain information. The cyclic analogue was found to induce experimental allergic encephalomyelitis (EAE), to bind HLA-DR4, and to increase CD4 T-cell line proliferation, like that of the conformationally related linear MBP87-99 epitope peptide. The mutant cyclic peptides, the cyclo(91−99)[Ala96]MBP87-99 and the cyclo(87−99)[Arg91Ala96]MBP87-99, reported previously for suppressing, to a varying degree, autoimmune encephalomyelitis in a rat animal model, were found in this study to possess the following immunomodulatory properties:  (i) they suppressed the proliferation of a CD4 T-cell line raised from a multiple sclerosis patient, (ii) they scored the best in vitro TH2/TH1 cytokine ratio in peripheral blood mononuclear cell cultures derived from 13 multiple sclerosis patients, inducing IL-10 selectively, and (iii) they bound to HLA-DR4, first to be reported for cyclic MBP peptides. In addition, cyclic peptides were found to be more stable to lysosomal enzymes and Cathepsin B, D, and H, compared to their linear counterparts. Taken together, these data render cyclic mimics as putative drugs for treating multiple sclerosis and potentially other Th1-mediated autoimmune diseases.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: Q Science > QD Chemistry
R Medicine > RS Pharmacy and materia medica
Publisher: American Chemical Society
ISSN: 0022-2623
Last Modified: 04 Jun 2017 03:12
URI: http://orca-mwe.cf.ac.uk/id/eprint/18098

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