Novel Approaches in the Immunotherapy of Multiple Sclerosis: Cyclization of Myelin Epitope Peptides and Conjugation with Mannan.

Thomas Mavromoustakos,Irene Ligielli,Konstantinos Kelaidonis,Vasso Apostolopoulos,Christos T. Chasapis,John M. Matsoukas

doi:10.3390/brainsci11121583

Abstract

Multiple Sclerosis (MS) is a serious autoimmune disease. The patient in an advanced state of the disease has restrained mobility and remains handicapped. It is therefore understandable that there is a great need for novel drugs and vaccines for the treatment of MS. Herein we summarise two major approaches applied for the treatment of the disease using peptide molecules alone or conjugated with mannan. The first approach focuses on selective myelin epitope peptide or peptide mimetic therapy alone or conjugated with mannan, and the second on immune-therapy by preventing or controlling disease through the release of appropriate cytokines. In both approaches the use of cyclic peptides offers the advantage of increased stability from proteolytic enzymes. In these approaches, the synthesis of myelin epitope peptides conjugated to mannan is of particular interest as this was found to protect mice against experimental autoimmune encephalomyelitis, an animal model of MS, in prophylactic and therapeutic protocols. Protection was peptide-specific and associated with reduced antigen-specific T cell proliferation. The aim of the studies of these peptide epitope analogs is to understand their molecular basis of interactions with human autoimmune T-cell receptor and a MS-associated human leucocyte antigen (HLA)-DR2b. This knowledge will lead the rational design to new beneficial non-peptide mimetic analogs for the treatment of MS. Some issues of the use of nanotechnology will also be addressed as a future trend to tackle the disease. We highlight novel immunomodulation and vaccine-based research against MS based on myelin epitope peptides and strategies developed in our laboratories.

Highlights

Multiple Sclerosis (MS) is a serious systemic demyelinating disease that leads to the partial paralysis of the patient who needs the assistance of medicare in order to survive with low quality of life
Spectroscopic data combined with Molecular Dynamics (MD) calculations showed that the linear MBP72–85 peptide adopts a pseudo-cyclic conformation
The results showed that peptides conjugated with mannan induce peripheral type 2 myeloid cell responses and T cell anergy, and suggests that mannan-peptide conjugates may be useful for suppressing antigen-specific CD4+ T-helper cell responses in the context of human autoimmune CNS demyelination [29]

Summary

Introduction

Multiple Sclerosis (MS) is a serious systemic demyelinating disease that leads to the partial paralysis of the patient who needs the assistance of medicare in order to survive with low quality of life. The application of MBP83–99-based altered peptide ligands inhibits MBP-reactive T cell proliferation in vitro [30]; this is attributed to anti-inflammatory Th2 cytokine secretion by T cells, primarily IL-4 and IL-10. Spectroscopic data combined with Molecular Dynamics (MD) calculations showed that the linear MBP72–85 peptide adopts a pseudo-cyclic conformation Based on this information, the cyclic analogue QKSQRSQDQNPV-NH2 was rationally designed. Brain Sci. 2021, 11, x FOR PEER REVIiEtsWlinear analogue and provides support to its proposed pseudo-cyclic conformatio6no.fI1n5 addition, this study proposes that a pseudo cyclic conformation for the MBP72–85 epitope allows D81 and K78 binding to the trimolecular complex MHC-peptide-TCR, and as a consequence, it inhibits EAE [23]. It is clear that cyclic modification of linear peptide counterparts may provide novel approaches for future, immunomodulative treatments against MS

Conjugation of Selective Epitopes with Mannan

Citrullination of MBP Derived Peptides Role in Disease

Non-Peptide Mimetic Analogs

Conclusions

Findings