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

Abstract

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 Arg

Myelin-derived and putative molecular mimic peptides share structural properties in aqueous and membrane-like environments

“…All our experiments point towards highly similar properties for all the studied peptides. In this respect, it is of interest to note the possible potential of myelin protein-derived peptides in MS therapy; these include both cyclic and mutated variants of myelin antigen peptides, especially MBP85-99 [59,[94][95][96][97][98]; the design of such peptides could also take into account our observations on similar overall structural and membrane interaction properties of peptides with limited sequence similarity per se. While the link between membrane binding, membraneinduced folding, and autoimmune response is unclear, molecular mimicry possibly taking place in autoimmune demyelination may be based on 3D similarity of host and pathogen epitopes.…”

“…Subtle differences in folding between the mMOG35-55 and hMOG35-55 epitopes may be relevant for inducing EAE with MOG peptides. Mutations in the mMOG35-55 peptide have also been linked to altered immune responses in mouse models [59]. Whether the recognition of the Pro/Ser residue itself or the variantfavored conformation determines the strength of autoimmunogenicity remains to be studied.…”

Molecular dynamics at the receptor level of immunodominant myelin oligodendrocyte glycoprotein 35–55 epitope implicated in multiple sclerosis

“…27,35 Our group has previously rationally designed and synthesized linear and cyclic peptide analogues of human MOG35-55 immunodominant epitope (hMOG35-55) with crucial TCR substitutions. 26 These altered peptides have proved to inhibit the clinical manifestation of symptoms of chronic EAE in mice. 26 The substitutions of Arg at positions 41 and 46 by Ala, result in peptide analogues that reduce the severity of MOG-induced EAE clinical symptoms in C57BL/6 mice when co-administered with mouse/rat MOG35-55 peptide at the time of immunization.…”

“…26 These altered peptides have proved to inhibit the clinical manifestation of symptoms of chronic EAE in mice. 26 The substitutions of Arg at positions 41 and 46 by Ala, result in peptide analogues that reduce the severity of MOG-induced EAE clinical symptoms in C57BL/6 mice when co-administered with mouse/rat MOG35-55 peptide at the time of immunization. 26 The observed results justify the importance of Arg at positions 41,46 for EAE induction.…”

“…24,25 The total myelin proteins consist of only 0.05%-0.1% of MOG; 24, 25 however MOG or MOG epitopes activate T-cell immune responses in Experimental Autoimmune Encephalomyelitis (EAE, animal model of MS) and have also been associated with MS induction. 26,27 There have been extensive studies of different fragments of MOG as autoimmune triggers. [28][29][30][31][32] The MOG epitopes 1-22, 61-80, 92-106 have been highlighted as target antigens and the 35-55 epitope has been found to induce highly specific antibodies reacting similar to the entire MOG protein.…”