X射线晶体学引导发现一种有效的双袋竞争性SIRT5抑制剂，用于对抗脓毒症相关的急性肾损伤
X-ray Crystallography-Guided Discovery of a Potent Dual-Pocket Competitive SIRT5 Inhibitor against Sepsis-Associated AKI.
摘要(中文译文)
脓毒症相关急性肾损伤（AKI）的管理仍是尚未满足的临床需求。SIRT5抑制显示出肾脏保护作用，提示其治疗潜力。利用SIRT5-先导化合物的共晶结构，我们合理设计了一类新型硝基乙烯类抑制剂，其可同时结合底物和NAD结合位点。优化后的抑制剂（IC = 0.29 μM）在两种脓毒症AKI小鼠模型中显著改善了肾功能（BUN和SCr）及组织病理学损伤。进一步的机制研究表明，其肾脏保护作用与抑制炎症相关，表现为血清CRP降低以及肾脏炎症细胞因子（IL-6、MCP-1、TNF-α）下调。重要的是，该化合物在相应治疗剂量下未显示出明显毒性。总之，本研究鉴定了一种新型SIRT5抑制剂，并证明了其针对脓毒症相关AKI的治疗潜力。
Abstract
Sepsis-associated acute kidney injury (AKI) management remains an unmet clinical need. SIRT5 inhibition shows renoprotective effects, suggesting its therapeutic potential. Using the cocrystal structure of SIRT5-lead compound , we rationally designed novel nitroethylene inhibitors that engage both the substrate and NAD binding sites. The optimized inhibitor (IC = 0.29 μM) produced significant improvements in renal function (BUN and SCr) and histopathological damage in two models of septic AKI mice. Further mechanistic studies showed that the renoprotective effects are linked to the suppression of inflammation, which was demonstrated by reduced serum CRP and downregulated renal inflammatory cytokines (IL-6, MCP-1, TNF-α). Importantly, showed no significant toxicity at the corresponding therapeutic dose. In summary, this study identifies a novel SIRT5 inhibitor and demonstrates its therapeutic potential against sepsis-associated AKI.
如何引用
AMA
Yingying Jiang, Lina Yang, Rui Xiong, Hang Zhang, Wenyi Liu, Ming Lei, et al. X-ray Crystallography-Guided Discovery of a Potent Dual-Pocket Competitive SIRT5 Inhibitor against Sepsis-Associated AKI.. Journal of medicinal chemistry. 2026; doi:10.1021/acs.jmedchem.5c03440.
APA
Yingying Jiang, Lina Yang, Rui Xiong, Hang Zhang, Wenyi Liu, Ming Lei, et al (2026). X-ray Crystallography-Guided Discovery of a Potent Dual-Pocket Competitive SIRT5 Inhibitor against Sepsis-Associated AKI.. Journal of medicinal chemistry. https://doi.org/10.1021/acs.jmedchem.5c03440
GB/T 7714
Yingying Jiang, Lina Yang, Rui Xiong, Hang Zhang, Wenyi Liu, Ming Lei, et al. X-ray Crystallography-Guided Discovery of a Potent Dual-Pocket Competitive SIRT5 Inhibitor against Sepsis-Associated AKI.[J]. Journal of medicinal chemistry, 2026 doi:10.1021/acs.jmedchem.5c03440.
在 PubMed增强版 阅读全文
翻译全文 · AI 文献问答 · PDF 原文下载 · 引用导出