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.
A cyclic analogue, [cyclo(87-99)MBP(87)(-)(99)], of the human immunodominant MBP(87)(-)(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 MBP(87)(-)(99) epitope peptide. The mutant cyclic peptides, the cyclo(91-99)[Ala(96)]MBP(87)(-)(99) and the cyclo(87-99)[Arg(91)Ala(96)]MBP(87)(-)(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.
Matsoukas
John
J
Department of Chemistry, University of Patras, Patras 26500, Greece. john.matsoukas@hotmail.com
Apostolopoulos
Vasso
V
Kalbacher
Hubert
H
Papini
Anna-Maria
AM
Tselios
Theodore
T
Chatzantoni
Kokona
K
Biagioli
Tiziana
T
Lolli
Francesco
F
Deraos
Spyros
S
Papathanassopoulos
Panagiotis
P
Troganis
Anastassios
A
Mantzourani
Efthimia
E
Mavromoustakos
Thomas
T
Mouzaki
Athanasia
A
D000276:Adjuvants, Immunologic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003500:Cyclization; D016207:Cytokines / Q000378:metabolism; D004355:Drug Stability; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology; D000939:Epitopes; D015804:HLA-DR4 Antigen / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology; D008958:Models, Molecular; D018716:Molecular Mimicry; D009103:Multiple Sclerosis / Q000097:blood / Q000276:immunology; D009154:Mutation; D004676:Myelin Basic Protein / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D011917:Rats, Inbred Lew; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism
D000276:Adjuvants, Immunologic; D016207:Cytokines; D000939:Epitopes; D015804:HLA-DR4 Antigen; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D010456:Peptides, Cyclic; C499141:cyclo(87-99)myelin basic protein (87-99); C115314:myelin basic protein 87-99