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<p>The inflammasome is a multimeric intracellular complex that regulates caspase-1 activity in innate immunity, with NLRP3 serving as a central mediator of inflammatory responses. Despite extensive efforts, effective inhibitors of NLRP3 oligomerization remain limited. Here, we screened a library of small molecules and identified four candidates that disrupt homo-oligomerization of the NLRP3 pyrin domain (PYD). Among these, compound E9 exhibited superior affinity and specificity, as confirmed by split-luciferase complementation assays, microscale thermophoresis (Kd &lt; 1 µM), molecular docking, and molecular dynamics simulations. Mechanistic analyses revealed that E9 binding induces targeted structural and dynamic remodeling of the PYD filament, dampening dominant collective motions and disrupting cooperative inter-subunit interactions. These changes reduce the filament’s conformational flexibility and impair its ability to recruit ASC, thereby inhibiting inflammasome activation in THP1-ASC-GFP cells, as evidenced by suppression of speck formation. Overall, our study identifies E9 as a potent inhibitor of NLRP3 oligomerization and highlights interface-specific modulation of filament dynamics as a promising strategy for developing next-generation inflammasome-targeted therapeutics.</p>

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Disruption of NLRP3 inflammasome assembly via ligand-induced remodeling of pyrin domain interfaces

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月9日

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  • Sara Khosravifard,
  • Saman Hosseinkhani,
  • Nuredin Bakhtiary,
  • Maryam Peyvandi,
  • Alexander S. S. Dömling

摘要

The inflammasome is a multimeric intracellular complex that regulates caspase-1 activity in innate immunity, with NLRP3 serving as a central mediator of inflammatory responses. Despite extensive efforts, effective inhibitors of NLRP3 oligomerization remain limited. Here, we screened a library of small molecules and identified four candidates that disrupt homo-oligomerization of the NLRP3 pyrin domain (PYD). Among these, compound E9 exhibited superior affinity and specificity, as confirmed by split-luciferase complementation assays, microscale thermophoresis (Kd < 1 µM), molecular docking, and molecular dynamics simulations. Mechanistic analyses revealed that E9 binding induces targeted structural and dynamic remodeling of the PYD filament, dampening dominant collective motions and disrupting cooperative inter-subunit interactions. These changes reduce the filament’s conformational flexibility and impair its ability to recruit ASC, thereby inhibiting inflammasome activation in THP1-ASC-GFP cells, as evidenced by suppression of speck formation. Overall, our study identifies E9 as a potent inhibitor of NLRP3 oligomerization and highlights interface-specific modulation of filament dynamics as a promising strategy for developing next-generation inflammasome-targeted therapeutics.