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Updated: May 19, 2026
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Published on: February 27, 2016
X-ray Crystallography-Guided Discovery of a Potent Dual-Pocket Competitive SIRT5 Inhibitor against Sepsis-Associated
Yingying Jiang1, Lina Yang2, Rui Xiong1
1Sichuan Provincial Engineering Research Center of Molecular Targeted Diagnostic & Therapeutic Drugs, School of Food and Bio-Engineering, Xihua University, Chengdu 610039, China.
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 1, we rationally designed novel nitroethylene inhibitors that engage both the substrate and NAD+ binding sites. The optimized inhibitor 56 (IC50 = 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, 56 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.