title: Single β³-amino acid substitutions to MOG peptides suppress the development of experimental autoimmune encephalomyelitis.
abstract: CD4(+) T-cells play a key role in the pathogenesis of multiple sclerosis (MS). Altered peptide ligands capable of modulating T-cell autoreactivity are considered a promising strategy for development of antigen-specific therapies for MS. Since peptides are inherently unstable, the current study explored single β-amino acid substitution as a means of stabilizing an epitope of myelin oligodendrocyte glycoprotein. β-Amino acid substitution at position 44, the major T-cell receptor contact residue, increased the half-life of active metabolites. Vaccination with one altered peptide, MOG44βF, conferred protection from EAE, decreased T-cell autoreactivity and pro-inflammatory cytokine production. Additional studies using MOG44βF in an oral treatment regimen, administered after EAE induction, also attenuated disease severity. Thus, altered peptides such as those reported here may lead to the development of novel and more specific treatments for MS.
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, 3800, Australia.
authors.forename: Courtney A
authors.initials: CA
authors.lastname: McDonald
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, 3800, Australia.
authors.forename: Natalie L
authors.initials: NL
authors.lastname: Payne
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, 3800, Australia.
authors.forename: Guizhi
authors.initials: G
authors.lastname: Sun
authors.affiliation: Department of Biochemistry & Molecular Biology, Monash University, Clayton 3800, Australia.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Clayton
authors.affiliation: Department of Biochemistry & Molecular Biology, Monash University, Clayton 3800, Australia.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Del Borgo
authors.affiliation: Department of Biochemistry & Molecular Biology, Monash University, Clayton 3800, Australia.
authors.forename: Marie-Isabel
authors.initials: MI
authors.lastname: Aguilar
authors.affiliation: School of Chemistry, Monash University, Clayton 3800, Australia.
authors.forename: Patrick
authors.initials: P
authors.lastname: Perlmutter
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, 3800, Australia. Electronic address: claude.bernard@monash.edu.
authors.forename: Claude C A
authors.initials: CC
authors.lastname: Bernard
mesh_terms: D019943:Amino Acid Substitution / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002490:Central Nervous System / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005620:Freund's Adjuvant / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000737:chemistry* / Q000187:drug effects / Q000633:toxicity*; D010446:Peptide Fragments / Q000737:chemistry / Q000187:drug effects / Q000627:therapeutic use* / Q000633:toxicity; D013601:T-Lymphocytes / Q000187:drug effects; D013997:Time Factors
chemical_list: D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D005620:Freund's Adjuvant
keywords: Altered peptide ligands; Beta-amino acid; Immunosuppressive; Multiple sclerosis; Myelin oligodendrocyte glycoprotein; Neuroinflammation