Discovery of digallic acid as XOD/URAT1 dual target inhibitor for the treatment of hyperuricemia

Bioorg Chem. 2024 Jun:147:107381. doi: 10.1016/j.bioorg.2024.107381. Epub 2024 Apr 23.

Abstract

The development of XOD/URAT1 dual target inhibitors has emerged as a promising therapeutic strategy for the management of hyperuricemia. Here, through virtual screening, we have identified digallic acid as a novel dual target inhibitor of XOD/URAT1 and subsequently evaluated its pharmacological properties, pharmacokinetics, and toxicities. Digallic acid inhibited URAT1 with an IC50 of 5.34 ± 0.65 μM, which is less potent than benzbromarone (2.01 ± 0.36 μM) but more potent than lesinurad (10.36 ± 1.23 μM). Docking and mutation analysis indicated that residues S35, F241 and R477 of URAT1 confer a high affinity for digallic acid. Digallic acid inhibited XOD with an IC50 of 1.04 ± 0.23 μM. Its metabolic product, gallic acid, inhibited XOD with an IC50 of 0.91 ± 0.14 μM. Enzyme kinetic studies indicated that both digallic acid and gallic acid act as mixed-type XOD inhibitors. It shares the same binding mode as digallic acid, and residues E802, R880, F914, T1010, N768 and F1009 contribute to their high affinity. The anion group (carboxyl) of digallic acid contribute significantly to its inhibition activity on both XOD and URAT1 as indicated by docking analysis. Remarkably, at a dosage of 10 mg/kg in vivo, digallic acid exhibited a stronger urate-lowering and uricosuric effect compared to the positive drug benzbromarone and lesinurad. Pharmacokinetic study indicated that digallic acid can be hydrolyzed into gallic acid in vivo and has a t1/2 of 0.77 ± 0.10 h. Further toxicity evaluation indicated that digallic acid exhibited no obvious renal toxicity, as reflected by CCK-8, biochemical analysis (CR and BUN) and HE examination. The findings of our study can provide valuable insights for the development of XOD/URAT1 dual target inhibitors, and digallic acid deserves further investigation as a potential anti-hyperuricemic drug.

Keywords: Gout; Hyperuricemia; Urate transporter 1; Xanthine oxidase.

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug*
  • Drug Discovery
  • Enzyme Inhibitors* / chemical synthesis
  • Enzyme Inhibitors* / chemistry
  • Enzyme Inhibitors* / pharmacokinetics
  • Enzyme Inhibitors* / pharmacology
  • Gallic Acid / analogs & derivatives
  • Gallic Acid / chemistry
  • Gallic Acid / pharmacology
  • Humans
  • Hyperuricemia* / drug therapy
  • Male
  • Mice
  • Molecular Docking Simulation
  • Molecular Structure
  • Organic Anion Transporters* / antagonists & inhibitors
  • Organic Anion Transporters* / metabolism
  • Organic Cation Transport Proteins* / antagonists & inhibitors
  • Organic Cation Transport Proteins* / metabolism
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Urate Oxidase / chemistry

Substances

  • SLC22A12 protein, human