PMID- 28594344 OWN - NLM STAT- MEDLINE DCOM- 20180326 LR - 20200306 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 18 IP - 6 DP - 2017 Jun 8 TI - Design and Synthesis of Non-Peptide Mimetics Mapping the Immunodominant Myelin Basic Protein (MBP(83-96)) Epitope to Function as T-Cell Receptor Antagonists. LID - 10.3390/ijms18061215 [doi] LID - 1215 AB - 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 MBP(83-96) 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-MBP(83-96) 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 MBP(83-99) 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. FAU - Yannakakis, Mary-Patricia AU - Yannakakis MP AD - Department of Chemistry, University of Patras, 26504 Rion Patras, Greece. yannakakism@gmail.com. AD - School of Chemistry, Cardiff University, Park Place, Cardiff CF103AT, Wales, UK. yannakakism@gmail.com. FAU - Simal, Carmen AU - Simal C AD - Department of Chemistry, University of Patras, 26504 Rion Patras, Greece. carmen.simal@gmail.com. FAU - Tzoupis, Haralambos AU - Tzoupis H AD - Department of Chemistry, University of Patras, 26504 Rion Patras, Greece. haralambostz@gmail.com. FAU - Rodi, Maria AU - Rodi M AD - Laboratory of Immunohematology, Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Rion, 26500 Patras, Greece. marodi_biol@yahoo.gr. FAU - Dargahi, Narges AU - Dargahi N AD - Centre for Chronic Disease, College of Health and Biomedicine, Victoria University, St. Albans, VIC 3021, Australia. Narges.dargahi@live.vu.edu.au. FAU - Prakash, Monica AU - Prakash M AD - Centre for Chronic Disease, College of Health and Biomedicine, Victoria University, St. Albans, VIC 3021, Australia. monica.prakash@vu.edu.au. FAU - Mouzaki, Athanasia AU - Mouzaki A AD - Laboratory of Immunohematology, Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Rion, 26500 Patras, Greece. mouzaki@upatras.gr. FAU - Platts, James A AU - Platts JA AD - School of Chemistry, Cardiff University, Park Place, Cardiff CF103AT, Wales, UK. platts@cardiff.ac.uk. FAU - Apostolopoulos, Vasso AU - Apostolopoulos V AD - Centre for Chronic Disease, College of Health and Biomedicine, Victoria University, St. Albans, VIC 3021, Australia. vasso.apostolopoulos@vu.edu.au. FAU - Tselios, Theodore V AU - Tselios TV AD - Department of Chemistry, University of Patras, 26504 Rion Patras, Greece. ttselios@upatras.gr. LA - eng PT - Journal Article DEP - 20170608 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Epitopes, T-Lymphocyte) RN - 0 (Myelin Basic Protein) RN - 0 (Peptide Fragments) RN - 0 (Receptors, Antigen, T-Cell) SB - IM MH - Amino Acid Sequence MH - Animals MH - *Biological Mimicry MH - Chemistry Techniques, Synthetic MH - Computer Simulation MH - *Drug Design MH - *Epitope Mapping MH - Epitopes, T-Lymphocyte/*chemistry/immunology/metabolism MH - Female MH - Humans MH - Leukocytes, Mononuclear/immunology/metabolism MH - Mice MH - Models, Molecular MH - Myelin Basic Protein/*chemistry/immunology MH - Peptide Fragments/chemical synthesis/*chemistry/immunology/pharmacology MH - Protein Binding MH - Protein Conformation MH - Receptors, Antigen, T-Cell/antagonists & inhibitors/*chemistry/metabolism PMC - PMC5486038 OTO - NOTNLM OT - T cell antagonism OT - cell proliferation OT - molecular modeling OT - multiple sclerosis OT - non-peptide mimetics OT - rational drug design OT - trimolecular complex COIS- The authors declare no conflict of interest. EDAT- 2017/06/09 06:00 MHDA- 2018/03/27 06:00 PMCR- 2017/06/01 CRDT- 2017/06/09 06:00 PHST- 2017/04/26 00:00 [received] PHST- 2017/06/02 00:00 [revised] PHST- 2017/06/02 00:00 [accepted] PHST- 2017/06/09 06:00 [entrez] PHST- 2017/06/09 06:00 [pubmed] PHST- 2018/03/27 06:00 [medline] PHST- 2017/06/01 00:00 [pmc-release] AID - ijms18061215 [pii] AID - ijms-18-01215 [pii] AID - 10.3390/ijms18061215 [doi] PST - epublish SO - Int J Mol Sci. 2017 Jun 8;18(6):1215. doi: 10.3390/ijms18061215.