title: Beyond knockout: A novel homodimerization-targeting MyD88 inhibitor prevents and cures type 1 diabetes in NOD mice.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China, Key Laboratory of Organ Transplantation, Ministry of Health, and Key Laboratory of Organ Transplantation, Ministry of Education.
authors: Xue
authors: X
authors: Zhang
authors: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China, Key Laboratory of Organ Transplantation, Ministry of Health, and Key Laboratory of Organ Transplantation, Ministry of Education; Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors: Shuai
authors: S
authors: Xing
authors: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China, Key Laboratory of Organ Transplantation, Ministry of Health, and Key Laboratory of Organ Transplantation, Ministry of Education; Department of surgery, Taian City Central Hospital, Taian, 271000, China.
authors: Mingqiang
authors: M
authors: Li
authors: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China, Key Laboratory of Organ Transplantation, Ministry of Health, and Key Laboratory of Organ Transplantation, Ministry of Education.
authors: Limin
authors: L
authors: Zhang
authors: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China, Key Laboratory of Organ Transplantation, Ministry of Health, and Key Laboratory of Organ Transplantation, Ministry of Education.
authors: Lin
authors: L
authors: Xie
authors: Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors: Wentao
authors: W
authors: He
authors: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China, Key Laboratory of Organ Transplantation, Ministry of Health, and Key Laboratory of Organ Transplantation, Ministry of Education.
authors: Jianhua
authors: J
authors: Liu
authors: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China, Key Laboratory of Organ Transplantation, Ministry of Health, and Key Laboratory of Organ Transplantation, Ministry of Education.
authors: Sheng
authors: S
authors: Chang
authors: Academy of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors: Fengchao
authors: F
authors: Jiang
authors: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China, Key Laboratory of Organ Transplantation, Ministry of Health, and Key Laboratory of Organ Transplantation, Ministry of Education. Electronic address: pzhou@tjh.tjmu.edu.cn.
authors: Ping
authors: P
authors: Zhou
mesh_terms: D000596:Amino Acids / Q000187:drug effects; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D005260:Female; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007113:Immunity, Innate / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors* / Q000235:genetics; D010179:Pancreas / Q000473:pathology; D010879:Piperazines / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013844:Thiazoles / Q000627:therapeutic use*
chemical_list: C000607343:5-(3-(4-(4-benzylpiperazin-1-yl)-N-(4-phenylthiazol-2-yl))propanamide; D000596:Amino Acids; D001786:Blood Glucose; D016207:Cytokines; D007004:Hypoglycemic Agents; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D010879:Piperazines; D013844:Thiazoles
keywords: DC; MyD88; MyD88 inhibitor; Therapeutics; Type 1 diabetes