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 article)

Matsoukas, J./ Apostolopoulos, V./ Kalbacher, H./ Papini, A. M./ Tselios, T./ Chatzantoni, K./ Biagioli, T./ Lolli, F./ Deraos, S./ Papathanassopoulos, P./ Troganis, A./ Mantzourani, E./ Mavromoustakos, T./ Mouzaki, A.


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 (Phe(89), Lys(91), Pro(96)) and HLA (His(88), Phe(90), Ile(93)) 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)[Ala(96)]MBP87-99 and the cyclo(87-99)[Are(91)Ala(96)]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.
Institution and School/Department of submitter: Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών και Τεχνολογιών. Τμήμα Βιολογικών Εφαρμογών και Τεχνολογιών
Keywords: experimental allergic encephalomyelitis,experimental autoimmune encephalomyelitis,terminal aromatic residue,altered peptide ligands,t-cell repertoire,multiple-sclerosis,angiotensin-ii,nonpeptide antagonists,self-peptide,ring cluster
URI: http://olympias.lib.uoi.gr/jspui/handle/123456789/7678
ISSN: 0022-2623
Link: <Go to ISI>://000227392200018
http://pubs.acs.org/doi/pdfplus/10.1021/jm040849g
Appears in Collections:Άρθρα σε επιστημονικά περιοδικά ( Ανοικτά)

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