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Design and synthesis of non-peptide mimetics mapping the immunodominant myelin basic protein (MBP83-96) epitope to function as T-Cell receptor antagonists

Yannakakis, Mary-Patricia, Simal, Carmen, Tzoupis, Haralambos, Rodi, Maria, Dargahi, Narges, Prakash, Monica, Mouzaki, Athanasia, Platts, James Alexis, Apostolopoulos, Vasso and Tselios, Theodore 2017. Design and synthesis of non-peptide mimetics mapping the immunodominant myelin basic protein (MBP83-96) epitope to function as T-Cell receptor antagonists. International Journal of Molecular Sciences 18 (6) , 1215. 10.3390/ijms18061215

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Advanced Research Computing @ Cardiff (ARCCA)
Subjects: Q Science > QD Chemistry
Uncontrolled Keywords: multiple sclerosis; trimolecular complex; rational drug design; non-peptide mimetics; molecular modeling; cell proliferation; T cell antagonism
Publisher: MDPI AG
ISSN: 1422-0067
Date of First Compliant Deposit: 20 June 2017
Date of Acceptance: 2 June 2017
Last Modified: 24 May 2018 14:51

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