X-ray Crystallography-Guided Discovery of a Potent Dual-Pocket Competitive SIRT5 Inhibitor against Sepsis-Associated AKI.

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.