Rational design and synthesis of altered peptide ligands based on human myelin oligodendrocyte glycoprotein 35-55 epitope: inhibition of chronic experimental autoimmune encephalomyelitis in mice.
Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease of the central nervous system and is an animal model of multiple sclerosis (MS). Although the etiology of MS remains unclear, there is evidence T-cell recognition of immunodominant epitopes of myelin proteins, such as the 35-55 epitope of myelin oligodendrocyte glycoprotein (MOG), plays a pathogenic role in the induction of chronic EAE. Cyclization of peptides is of great interest since the limited stability of linear peptides restricts their potential use as therapeutic agents. Herein, we have designed and synthesized a number of linear and cyclic peptides by mutating crucial T cell receptor (TCR) contact residues of the human MOG35-55 epitope. In particular, we have designed and synthesized cyclic altered peptide ligands (APLs) by mutating Arg41 with Ala or Arg41 and Arg46 with Ala. The peptides were synthesized in solid phase on 2-chlorotrityl chloride resin (CLTR-Cl) using the Fmoc/t-Bu methodology. The purity of final products was verified by RP-HPLC and their identification was achieved by ESI-MS. It was found that the substitutions of Arg at positions 41 and 46 with Ala results in peptide analogues that reduce the severity of MOG-induced EAE clinical symptoms in C57BL/6 mice when co-administered with mouse MOG35-55 peptide at the time of immunization.
Department of Chemistry, University of Patras, 26500 Patras, Greece. ttselios@upatras.gr.
Theodore
T
Tselios
Department of Chemistry, University of Patras, 26500 Patras, Greece. mihalis_ali@hotmail.com.
Mihalis
M
Aggelidakis
Department of Chemistry, University of Patras, 26500 Patras, Greece. atapeinou@upatras.gr.
Anthi
A
Tapeinou
Department of Molecular Genetics, Hellenic Pasteur Institute, 11521 Athens, Greece. vtseveleki@pasteur.gr.
Vivian
V
Tseveleki
Department of Molecular Genetics, Hellenic Pasteur Institute, 11521 Athens, Greece. ikanistras@pasteur.gr.
Ioannis
I
Kanistras
Department of Chemistry, University of Patras, 26500 Patras, Greece. d.gatos@upatras.gr.
Dimitrios
D
Gatos
Department of Chemistry, University of Patras, 26500 Patras, Greece. imats@upatras.gr.
John
J
Matsoukas
D000595:Amino Acid Sequence; D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000378:metabolism; D000939:Epitopes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000378:metabolism; D009185:Myelin Proteins / Q000737:chemistry / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000737:chemistry* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014320:Triphenylmethyl Compounds / Q000737:chemistry
D000939:Epitopes; D008024:Ligands; C571326:MOG protein, human; D009185:Myelin Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D014320:Triphenylmethyl Compounds; C071065:2-chlorotrityl chloride