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

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

  • J Med Chem. 2026 May 28;69(10):11926-11947. doi: 10.1021/acs.jmedchem.5c03440.
Yingying Jiang 1,  Lina Yang 2,  Rui Xiong 1,  Hang Zhang 1,  Wenyi Liu 1,  Ming Lei 3,  Pengcheng Lei 1,  Zhiwen Yang 1,  Yanjun Wang 1,  Hui Lei 1,  Rong Li 4,  Zhouyu Wang 5,  Guo-Bo Li 4,  Liang Ma 2,  Lingling Yang 1
Affiliations

Affiliations

  • 1 Sichuan Provincial Engineering Research Center of Molecular Targeted Diagnostic & Therapeutic Drugs, School of Food and Bio-Engineering, Xihua University, Chengdu 610039, China.
  • 2 Division of Nephrology, Institute of Kidney Diseases, West China Hospital of Sichuan University, Chengdu 610041, China.
  • 3 Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, U.K.
  • 4 Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
  • 5 College of Science, Xihua University, Chengdu, Sichuan 610039, China.
PMID: 42143779 DOI: 10.1021/acs.jmedchem.5c03440
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.

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