Design of Linear and Cyclic Mutant Analogues of Dirucotide Peptide (MBP82⁻98) against Multiple Sclerosis: Conformational and Binding Studies to MHC Class II.

George Deraos,Konstantina Christopoulou,Hubert Kalbacher,John Matsoukas,Eftichia Kritsi,Vasso Apostolopoulos,Minos-Timotheos Matsoukas,Panagiotis Zoumpoulakis

doi:10.3390/brainsci8120213

Abstract

Background: Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system. MS is a T cell-mediated disease characterized by the proliferation, infiltration, and attack of the myelin sheath by immune cells. Previous studies have shown that cyclization provides molecules with strict conformation that could modulate the immune system. Methods: In this study, we synthesized peptide analogues derived from the myelin basic protein (MBP)82–98 encephalitogenic sequence (dirucotide), the linear altered peptide ligand MBP82–98 (Ala91), and their cyclic counterparts. Results: The synthesized peptides were evaluated for their binding to human leukocyte antigen (HLA)-DR2 and HLA-DR4 alleles, with cyclic MBP82–98 being a strong binder with the HLA-DR2 allele and having lower affinity binding to the HLA-DR4 allele. In a further step, conformational analyses were performed using NMR spectroscopy in solution to describe the conformational space occupied by the functional amino acids of both linear and cyclic peptide analogues. This structural data, in combination with crystallographic data, were used to study the molecular basis of their interaction with HLA-DR2 and HLA-DR4 alleles. Conclusion: The cyclic and APL analogues of dirucotide are promising leads that should be further evaluated for their ability to alter T cell responses for therapeutic benefit against MS.

Highlights

Multiple sclerosis (MS) is a chronic neurodegenerative disease that affects protein constituents within the myelin sheath, such as myelin basic protein (MBP), myelin oligodendrocyte glycoprotein, and proteolipid protein
altered peptide ligands (APL) closely resemble their native peptide, with one to two altered amino acid residues; usually for autoimmunity, they closely resemble those that interact with the T cell receptor (TCR) [24] as opposed to changes to residues within the peptide-binding groove, which is commonly altered for cancer peptides [25,26]
Studies showed that mutations to the peptide MBP72–85, which is an immunodominant epitope in Lewis rats, inhibited the stimulation of T cells and the clinical progression of EAE [27]

Summary

Introduction

Multiple sclerosis (MS) is a chronic neurodegenerative disease that affects protein constituents within the myelin sheath, such as myelin basic protein (MBP), myelin oligodendrocyte glycoprotein, and proteolipid protein. Brain Sci. 2018, 8, 213 helper (h) 1 cells mediating disease, which recognize peptide epitopes such as MBP83–99 , MBP87–99 , and MBP1–22. These agonist peptide epitopes and their altered peptide ligands (APL; mutation by one to two amino acids) have been extensively studied by our group and others for their ability to modulate immune responses [1–10] and/or inhibit experimental autoimmune encephalomyelitis (EAE), which is one of the best animal models to study MS. Cyclic peptides are considered as mimetic candidates of their linear relatives and as modulators of immune cells. MS is a T cell-mediated disease characterized by the proliferation, infiltration, and attack of the myelin sheath by immune cells.

Methods

Results

Conclusion