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Background <p>Marine-derived microorganisms are renowned for producing structurally diverse secondary metabolites with notable biological activities, serving as a promising reservoir for pharmaceutical development. In this study, the fungal strain <i>Westerdykella dispersa</i> Ca4-13, isolated from the edible oyster <i>Crassostrea angulata</i>, was investigated for its potential anti-inflammatory and cytoprotective properties using BV-2 microglial cells as a model system.</p> Results <p>Metabolite profiling of the solid-state fermented products of <i>W. dispersa</i> Ca4-13 yielded seven compounds <b>1</b>–<b>7</b>. Their structures were elucidated using NMR and MS techniques, revealing three previously undescribed cytochalasins, namely westerchalasin A (<b>1</b>), westerchalasin B (<b>2</b>), and westerchalasin C (<b>3</b>), along with four known compounds <b>4</b>–<b>7</b>. Among these, westerchalasin B (<b>2</b>) and westerchalasin C (<b>3</b>) significantly exhibited nitric oxide (NO) production production in LPS-stimulated BV-2 microglial cells, with IC₅₀ values of 11.1 ± 0.4 and 9.9 ± 0.4 µM, respectively. Western blot analysis demonstrated that compounds <b>2</b> and <b>3</b> significantly downregulated inducible nitric oxide synthase (iNOS) expression at a concentration of 20 µM. Moreover, molecular docking analysis revealed that compound <b>3</b> exhibited a high binding affinity for iNOS synthase (ΔG = -18.8104&#xa0;kcal/mol). The strong interaction was attributed to of hydrogen bonds between the catalytic residue Arg375 and the C-18 carbonyl group of the cycloundecene moiety, as well as Pi-alkyl interactions with Trp367, which contributed to enhanced stability of the complex.</p> Conclusions <p>This study reported the isolation and structural elucidation of three novel cytochalasins <b>1</b>–<b>3</b> from <i>W. dispersa</i> Ca4-13. Notably, compounds <b>2</b> and <b>3</b> demonstrated anti-inflammatory activity by inhibiting NO production and iNOS expression in LPS-stimulated BV-2 microglial cells. Molecular docking analysis further confirmed strong interactions between compound <b>3</b> and key iNOS residues. Given the crucial role of neuroinflammation in neurodegenerative disorders, these findings suggested that compounds <b>2</b> and <b>3</b> may possess dual neuroprotective properties, warranting further exploration for therapeutic applications.</p>

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Novel inducible nitric oxide synthase-inhibiting cytochalasins from an oyster-derived fungus Westerdykella dispersa Ca4-13: structural insights and molecular docking analysis

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  • 发表日期：

    2025年10月7日

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  • Shu-Jung Huang,
  • Su-Jung Hsu,
  • Shih-Wei Wang,
  • Yi-Chien Liu,
  • Cheng-Yan Jiang,
  • George Hsiao,
  • Tzong-Huei Lee

摘要

Background

Marine-derived microorganisms are renowned for producing structurally diverse secondary metabolites with notable biological activities, serving as a promising reservoir for pharmaceutical development. In this study, the fungal strain Westerdykella dispersa Ca4-13, isolated from the edible oyster Crassostrea angulata, was investigated for its potential anti-inflammatory and cytoprotective properties using BV-2 microglial cells as a model system.

Results

Metabolite profiling of the solid-state fermented products of W. dispersa Ca4-13 yielded seven compounds 1–7. Their structures were elucidated using NMR and MS techniques, revealing three previously undescribed cytochalasins, namely westerchalasin A (1), westerchalasin B (2), and westerchalasin C (3), along with four known compounds 4–7. Among these, westerchalasin B (2) and westerchalasin C (3) significantly exhibited nitric oxide (NO) production production in LPS-stimulated BV-2 microglial cells, with IC₅₀ values of 11.1 ± 0.4 and 9.9 ± 0.4 µM, respectively. Western blot analysis demonstrated that compounds 2 and 3 significantly downregulated inducible nitric oxide synthase (iNOS) expression at a concentration of 20 µM. Moreover, molecular docking analysis revealed that compound 3 exhibited a high binding affinity for iNOS synthase (ΔG = -18.8104 kcal/mol). The strong interaction was attributed to of hydrogen bonds between the catalytic residue Arg375 and the C-18 carbonyl group of the cycloundecene moiety, as well as Pi-alkyl interactions with Trp367, which contributed to enhanced stability of the complex.

Conclusions

This study reported the isolation and structural elucidation of three novel cytochalasins 1–3 from W. dispersa Ca4-13. Notably, compounds 2 and 3 demonstrated anti-inflammatory activity by inhibiting NO production and iNOS expression in LPS-stimulated BV-2 microglial cells. Molecular docking analysis further confirmed strong interactions between compound 3 and key iNOS residues. Given the crucial role of neuroinflammation in neurodegenerative disorders, these findings suggested that compounds 2 and 3 may possess dual neuroprotective properties, warranting further exploration for therapeutic applications.