Structure-based selection of small molecules to alter allele-specific MHC class II antigen presentation

AW Michels, DA Ostrov, L Zhang… - The Journal of …, 2011 - journals.aai.org
AW Michels, DA Ostrov, L Zhang, M Nakayama, M Fuse, K McDaniel, BO Roep, PA Gottlieb
The Journal of Immunology, 2011journals.aai.org
Class II major histocompatibility molecules are the primary susceptibility locus for many
autoimmune disorders, including type 1 diabetes. Human DQ8 and IA g7, in the NOD mouse
model of spontaneous autoimmune diabetes, confers diabetes risk by modulating
presentation of specific islet peptides in the thymus and periphery. We used an in silico
molecular docking program to screen a large “druglike” chemical library to define small
molecules capable of occupying specific structural pockets along the IA g7 binding groove …
Abstract
Class II major histocompatibility molecules are the primary susceptibility locus for many autoimmune disorders, including type 1 diabetes. Human DQ8 and IA g7, in the NOD mouse model of spontaneous autoimmune diabetes, confers diabetes risk by modulating presentation of specific islet peptides in the thymus and periphery. We used an in silico molecular docking program to screen a large “druglike” chemical library to define small molecules capable of occupying specific structural pockets along the IA g7 binding groove, with the objective of influencing presentation to T cells of the autoantigen insulin B chain peptide consisting of amino acids 9–23. In this study we show, using both murine and human cells, that small molecules can enhance or inhibit specific TCR signaling in the presence of cognate target peptides, based upon the structural pocket targeted. The influence of compounds on the TCR response was pocket dependent, with pocket 1 and 6 compounds inhibiting responses and molecules directed at pocket 9 enhancing responses to peptide. At nanomolar concentrations, the inhibitory molecules block the insulin B chain peptide consisting of amino acids 9–23, endogenous insulin, and islet-stimulated T cell responses. Glyphosine, a pocket 9 compound, enhances insulin peptide presentation to T cells at concentrations as low as 10 nM, upregulates IL-10 secretion, and prevents diabetes in NOD mice. These studies present a novel method for identifying small molecules capable of both stimulating and inhibiting T cell responses, with potentially therapeutic applications.
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