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

Molecules

Theodore Tselios¹  Mihalis Aggelidakis¹  Anthi Tapeinou¹  Vivian Tseveleki²  Ioannis Kanistras²  Dimitrios Gatos¹  John Matsoukas¹ 

[1]Department of Chemistry, University of Patras, 26500 Patras, Greece

[2] E-Mails:

[3]Department of Molecular Genetics, Hellenic Pasteur Institute, 11521 Athens, Greece

[4] E-Mails:

关键词: multiple sclerosis;    experimental autoimmune encephalomyelitis;    altered peptide ligand;    cyclic peptides;   

DOI  :  10.3390/molecules191117968

来源: mdpi

【 摘 要 】

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 MOG_35–55 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 MOG_35–55 peptide at the time of immunization.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.