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

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.