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Small-molecule antagonism of the interaction of the RAGE cytoplasmic domain with DIAPH1 reduces diabetic complications in mice
Science Translational Medicine ( IF 17.1 ) Pub Date : 2021-11-24 , DOI: 10.1126/scitranslmed.abf7084
Michaele B Manigrasso 1 , Piul Rabbani 2 , Lander Egaña-Gorroño 1 , Nosirudeen Quadri 1 , Laura Frye 1 , Boyan Zhou 3 , Sergey Reverdatto 4 , Lisa S Ramirez 4 , Stephen Dansereau 4 , Jinhong Pan 4 , Huilin Li 3 , Vivette D D'Agati 5 , Ravichandran Ramasamy 1 , Robert J DeVita 6 , Alexander Shekhtman 4 , Ann Marie Schmidt 1
Affiliation  

The macro- and microvascular complications of type 1 and 2 diabetes lead to increased disease severity and mortality. The receptor for advanced glycation end products (RAGE) can bind AGEs and multiple proinflammatory ligands that accumulate in diabetic tissues. Preclinical studies indicate that RAGE antagonists have beneficial effects on numerous complications of diabetes. However, these antagonists target the extracellular domains of RAGE, which bind distinct RAGE ligands at diverse sites in the immunoglobulin-like variable domain and two constant domains. The cytoplasmic tail of RAGE (ctRAGE) binds to the formin, Diaphanous-1 (DIAPH1), and this interaction is important for RAGE signaling. To comprehensively capture the breadth of RAGE signaling, we developed small-molecule antagonists of ctRAGE-DIAPH1 interaction, termed RAGE229. We demonstrated that RAGE229 is effective in suppressing RAGE-DIAPH1 binding, Förster resonance energy transfer, and biological activities in cellular assays. Using solution nuclear magnetic resonance spectroscopy, we defined the molecular underpinnings of the interaction of RAGE229 with RAGE. Through in vivo experimentation, we showed that RAGE229 assuaged short- and long-term complications of diabetes in both male and female mice, without lowering blood glucose concentrations. Last, the treatment with RAGE229 reduced plasma concentrations of TNF-α, IL-6, and CCL2/JE-MCP1 in diabetic mice, in parallel with reduced pathological and functional indices of diabetes-like kidney disease. Targeting ctRAGE-DIAPH1 interaction with RAGE229 mitigated diabetic complications in rodents by attenuating inflammatory signaling.

中文翻译:

RAGE 胞质结构域与 DIAPH1 相互作用的小分子拮抗作用可减少小鼠糖尿病并发症

1 型和 2 型糖尿病的大血管和微血管并发症导致疾病严重程度和死亡率增加。晚期糖基化终产物 (RAGE) 的受体可以结合 AGE 和糖尿病组织中积累的多种促炎配体。临床前研究表明,RAGE 拮抗剂对多种糖尿病并发症具有有益作用。然而,这些拮抗剂靶向 RAGE 的胞外结构域,其在免疫球蛋白样可变结构域和两个恒定结构域的不同位点结合不同的 RAGE 配体。RAGE (ctRAGE) 的细胞质尾部与福尔明、Diaphanous-1 (DIAPH1) 结合,这种相互作用对于 RAGE 信号转导非常重要。为了全面捕获 RAGE 信号传导的广度,我们开发了 ctRAGE-DIAPH1 相互作用的小分子拮抗剂,称为 RAGE229。我们证明,RAGE229 可有效抑制 RAGE-DIAPH1 结合、Förster 共振能量转移和细胞测定中的生物活性。使用溶液核磁共振波谱,我们定义了 RAGE229 与 RAGE 相互作用的分子基础。通过体内实验,我们表明 RAGE229 可以减轻雄性和雌性小鼠的短期和长期糖尿病并发症,而不会降低血糖浓度。最后,RAGE229 治疗降低了糖尿病小鼠体内 TNF-α、IL-6 和 CCL2/JE-MCP1 的血浆浓度,同时降低了糖尿病样肾病的病理和功能指数。靶向 ctRAGE-DIAPH1 与 RAGE229 的相互作用可通过减弱炎症信号来减轻啮齿类动物的糖尿病并发症。
更新日期:2021-11-25
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