Design and Synthesis of Non-Peptide Mimetics Mapping the Immunodominant Myelin Basic Protein (MBP83–96) Epitope to Function as T-Cell Receptor Antagonists

Abstract

Encephalitogenic T cells are heavily implicated in the pathogenesis of multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system. Their stimulation is triggered by the formation of a trimolecular complex between the human leukocyte antigen (HLA), an immunodominant myelin basic protein (MBP) epitope, and the T cell receptor (TCR). We detail herein our studies directed towards the rational design and synthesis of non-peptide mimetic molecules, based on the immunodominant MBP83–96 epitope that is recognized by the TCR in complex with HLA. We focused our attention on the inhibition of the trimolecular complex formation and consequently the inhibition of proliferation of activated T cells. A structure-based pharmacophore model was generated, in view of the interactions between the TCR and the HLA-MBP83–96 complex. As a result, new candidate molecules were designed based on lead compounds obtained through the ZINC database. Moreover, semi-empirical and density functional theory methods were applied for the prediction of the binding energy between the proposed non-peptide mimetics and the TCR. We synthesized six molecules that were further evaluated in vitro as TCR antagonists. Analogues 15 and 16 were able to inhibit to some extent the stimulation of T cells by the immunodominant MBP83–99 peptide from immunized mice. Inhibition was followed to a lesser degree by analogues 17 and 18 and then by analogue 19. These studies show that lead compounds 15 and 16 may be used for immunotherapy against MS.

Multiple Sclerosis: Immunopathology and Treatment Update

“…As described here a number of new and upcoming promising therapeutic candidates are becoming available, although their effectiveness in human clinical trials remains to be determined. Recently, it was reported that non-peptide mimetics mapping the MBP [83][84][85][86][87][88][89][90][91][92][93][94][95][96] T cell epitope can function as T cell receptor antagonists, hence such an approach may pave the way to developing alternative and improved immunotherapeutics against MS [189]. With the plethora of information regarding the immunopathophysiology of MS and availability of treatment options and new upcoming treatments, the future holds promise for managing and treating the disease.…”

Streptococcus thermophilus ST285 Alters Pro-Inflammatory to Anti-Inflammatory Cytokine Secretion against Multiple Sclerosis Peptide in Mice

“…The MBP 83-99 mannan peptide conjugate (50 µg/mouse) was injected in the SJL/J mice subcutaneously into the base of the tail, three times, every two weeks [17]. This conjugate has been shown to induce T cell proliferation and IFN-γ cytokine secretion to the agonist MBP 83-99 peptide in SJL/J mice [17,19,23,24]. Ten to fourteen days after the three injections, spleen cells were isolated, red blood cells were lysed using 0.73% NH 4 Cl, and counted.…”

“…In SJL/J mice, immunization with the MBP 83-99 peptide mixed with mycobacterium stimulates autoimmune CD4 + T cells in mice, and induces EAE [7,17]. Major histocompatibility complex (MHC) class II H-2 s haplotype in the SJL/J mouse strain resembles many clinical, histopathological, and immunological characteristics of human MS, thus the SJL/J mouse is regularly used for immunization studies.…”

“…Major histocompatibility complex (MHC) class II H-2 s haplotype in the SJL/J mouse strain resembles many clinical, histopathological, and immunological characteristics of human MS, thus the SJL/J mouse is regularly used for immunization studies. Different peptides are immunogenic in different mouse strains however, in the SJL/J mouse strain, the peptide MBP 81-100 binds to MHC class II H-2 s with high affinity with the minimum epitope being MBP 83-99 [7,17]. As such, the MBP 83-99 epitope has been used as an agonist peptide to immunize mice for the activation of CD4 + T cells [7,17].…”

“…Different peptides are immunogenic in different mouse strains however, in the SJL/J mouse strain, the peptide MBP 81-100 binds to MHC class II H-2 s with high affinity with the minimum epitope being MBP 83-99 [7,17]. As such, the MBP 83-99 epitope has been used as an agonist peptide to immunize mice for the activation of CD4 + T cells [7,17]. We have shown that injection of the MBP 83-99 peptide conjugated to the carrier mannan or mixed in complete Freund's adjuvant induces Th1 pro-inflammatory interferon-gamma (IFN γ-g) secreting CD4 + T cells [18][19][20][21][22][23][24][25].…”