2. Academic Validation
  3. Optimization of Ascidian-Derived Herdmanine D: Targeting Gouty Arthritis via the PPAR-γ/NF-κB/NLRP3 Pathway

Optimization of Ascidian-Derived Herdmanine D: Targeting Gouty Arthritis via the PPAR-γ/NF-κB/NLRP3 Pathway

  • J Med Chem. 2026 Jan 8;69(1):683-697. doi: 10.1021/acs.jmedchem.5c03246.
Xinlin Zhu 1,  Yi Dong 1,  Ya Zhang 2,  Chenghai Gao 3,  Lijian Ding 4,  Yonghong Liu 3,  Zhiran Ju 1
Affiliations

Affiliations

  • 1 Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, State Key Laboratory of Green Chemical Synthesis and Conversion, Zhejiang University of Technology, Hangzhou 310000, China.
  • 2 Treatment Center & Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
  • 3 Institute of Marine Drugs, Guangxi University of Chinese Medicine, Nanning 530200, China.
  • 4 School of Pharmacy, Health Science Center, Ningbo University, Ningbo 315211, China.
PMID: 41439522 DOI: 10.1021/acs.jmedchem.5c03246
Abstract

Gouty arthritis, driven by monosodium urate (MSU) crystal deposition and dysregulated inflammation, remains a therapeutic challenge due to the limitations of current treatments. Here, we investigate Herdmanine D (HDD), a marine-derived alkaloid from the ascidian Herdmania momus. It was optimized via structure-activity relationship (SAR) studies and computational modeling to enhance its binding to Peroxisome Proliferator-activated Receptor γ (PPAR-γ), which regulates the PPAR-γ/NF-κB signaling pathway in gout pathogenesis. The optimized HDD derivative 9a demonstrated potent PPAR-γ binding affinity and pharmacokinetic properties, effectively suppressing NF-κB-driven pro-inflammatory cytokines in vitro. In murine MSU-induced gouty arthritis models, 9a alleviated synovial inflammation and tissue damage. Mechanistically, 9a activated PPAR-γ to inhibit NF-κB and attenuate NLRP3 inflammasome assembly. This work highlights HDD as a unique marine scaffold for next-generation antigout therapeutics, merging marine natural product safety with rational design to address unmet clinical needs.

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