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.
Highlights
Multiple sclerosis (MS) is an immunologically controlled, inflammatory, demyelinating disease, described as the destruction of the myelin sheath of the central nervous system, which can lead to paralysis [1,2]
The results show that analogue 15 was the most effective T cell receptor (TCR) antagonist, i.e., it conferred the highest inhibition of T cell proliferation (Figure 7b)
As we have previously shown that the native peptide MBP83–99 conjugated to mannan induces strong proliferative T cells to recall MBP83–99 peptide, we used 3 mice/group to test each of the compounds’ ability to inhibit this T cell proliferation
Summary
Multiple sclerosis (MS) is an immunologically controlled, inflammatory, demyelinating disease, described as the destruction of the myelin sheath of the central nervous system, which can lead to paralysis [1,2]. In the context of MS, encephalitogenic T cells are activated through the formation of a trimolecular complex between the T cell receptor (TCR), a short 14–18 amino acid myelin peptide (epitope), and the major histocompatibility complex (MHC) class II. The MHC class II (HLA) consists of dimers (the α chain and the β chain) [9,10], which present short antigenic peptide epitopes to CD4+ Th cells, resulting in the formation of the trimolecular complex (HLA-peptide-TCR). CDRs are implicated in the recognition of the TCR to HLA-peptide complex, and their structural diversity plays a crucial role in the recognition of the different antigens presented to T cells by antigen presenting cells [11,12]. The rigorous positive and negative selection process of T cells in the thymus does not prevent auto-reactive T cells from escaping thymic deletion [13,14,15], initiating the development of autoimmune disorders such as MS
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