Beyond knockout: A novel homodimerization-targeting MyD88 inhibitor prevents and cures type 1 diabetes in NOD mice

Metabolism. 2016 Sep;65(9):1267-77. doi: 10.1016/j.metabol.2016.05.005. Epub 2016 May 14.

Abstract

Introduction and aims: Studies have reported that myeloid differentiation factor 88 (MyD88) plays an important role in the development of type 1 diabetes (T1D). The aim of this study was to determine the effects of the self-created MyD88 inhibitor, TJ-M2010-6, in preventing and treating T1D.

Methods: Molecule docking and co-immunoprecipitation were used to determine the suppressing capability of TJ-M2010-6 on the homodimerization of MyD88. The preventive and therapeutic effects of TJ-M2010-6 were tested in NOD mice.

Results: TJ-M2010-6 interacted with amino acid residues of the MyD88 TIR domain and inhibited MyD88 homodimerization. Continuous administration of TJ-M2010-6 significantly reduced the onset of diabetes during the observation period in NOD mice (36.4% vs. 80%, P<0.01). Although the immediate TJ-M2010-6 treatment group showed a retardation in the rise of their blood glucose level, the delayed treatment group did not show this effect. Mechanism studies have shown that TJ-M2010-6 treatment significantly inhibits insulitis in vivo. In vitro, TJ-M2010-6 inhibited the maturation of DCs, leading to the suppression of T cell activation and inflammatory cytokine secretion.

Conclusions: These results demonstrated that the strategy targeted at the innate immune system using the MyD88 inhibitor had a profound significance in preventing and treating T1D.

Keywords: DC; MyD88; MyD88 inhibitor; Therapeutics; Type 1 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / drug effects
  • Animals
  • Blood Glucose / metabolism
  • Cytokines / biosynthesis
  • Dendritic Cells / drug effects
  • Dendritic Cells / metabolism
  • Diabetes Mellitus, Type 1 / drug therapy*
  • Diabetes Mellitus, Type 1 / pathology
  • Diabetes Mellitus, Type 1 / prevention & control
  • Female
  • Hypoglycemic Agents / therapeutic use*
  • Immunity, Innate / drug effects
  • Lymphocyte Activation / drug effects
  • Mice
  • Mice, Inbred NOD
  • Mice, Knockout
  • Models, Molecular
  • Molecular Docking Simulation
  • Myeloid Differentiation Factor 88 / antagonists & inhibitors*
  • Myeloid Differentiation Factor 88 / genetics
  • Pancreas / pathology
  • Piperazines / therapeutic use*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • Thiazoles / therapeutic use*

Substances

  • 5-(3-(4-(4-benzylpiperazin-1-yl)-N-(4-phenylthiazol-2-yl))propanamide
  • Amino Acids
  • Blood Glucose
  • Cytokines
  • Hypoglycemic Agents
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Piperazines
  • Thiazoles