TH5487 specifically targets NLRP3 in FCAS patients resistant to MCC950

Area of Science:

• Immunology
• Molecular Biology
• Drug Discovery

Background:

• Aberrant activation of the NLRP3 inflammasome is implicated in numerous chronic inflammatory disorders.
• Targeting inflammasome pathways presents a therapeutic avenue for inflammatory conditions.

Purpose of the Study:

• To investigate the potential of small-molecule inhibitors of the DNA repair enzyme 7,8-dihydro-8-oxoguanine triphosphate hydrolase 1 (hOGG1) to inhibit NLRP3 inflammasome activation.
• To explore a novel mechanism for regulating inflammasome activity through interference with oxidized DNA sensing.

Main Methods:

• Utilized small-molecule inhibitors targeting hOGG1 in human cell lines and peripheral blood mononuclear cells (PBMCs).
• Assessed IL-1β secretion and type I interferon responses.
• Employed Cryo-electron microscopy (Cryo-EM) for structural analysis of NLRP3-DNA interactions.
• Performed structural modeling to predict interactions with oxidized DNA (oxDNA).
• Tested inhibitor efficacy in patient-derived PBMCs with FCAS mutations and in mouse models.

Main Results:

• hOGG1 inhibitors, such as TH5487, effectively reduced IL-1β secretion and enhanced type I interferon responses in human cells.
• Cryo-EM revealed a direct association between NLRP3 and mitochondrial DNA.
• Structural modeling suggested interaction between NLRP3 and oxDNA.
• hOGG1 inhibitors demonstrated efficacy in patient-derived cells and mouse models, even where MCC950 was ineffective.

Conclusions:

• Small-molecule inhibitors of hOGG1 represent a novel class of NLRP3 inflammasome inhibitors.
• Interference with oxidized DNA sensing by NLRP3 offers a new druggable target for managing inflammatory diseases.
• These findings provide innovative therapeutic opportunities for autoinflammatory disorders.