NLRP3 inhibitors(Bengbu Medical College)

Targeting the NLRP3 inflammasome has become an attractive therapeutic strategy for a wide range of inflammatory and immune-mediated diseases due to its central role in innate immunity and pathological inflammation. In this study, a series of novel grandiflorenic acid derivatives were rationally designed and semisynthesized as effective covalent NLRP3 inhibitors. These compounds inhibited IL-1β release in the nanomolar range, with compound 5 identified as the most potent derivative of the series (IC₅₀ = 1.36 ± 0.21 nM). Several selected derivatives (4, 5, 8, 17, 20 and 21) markedly reduced IL-1β release following activation by diverse stimuli, including nigericin, ATP, imiquimod, or MSU crystals, demonstrating a strong and stimulus-independent inhibition of NLRP3 signaling. Additionally, representative compounds 5, 8, and 17 significantly decreased LDH release, indicating effective suppression of inflammasome-mediated pyroptosis. Molecular dynamic simulations confirmed the stable binding of compound 5 within the ATP-binding site of NLRP3. In silico ADME analysis further predicted good human oral absorption for compounds 4, 5, 8, 17, 20 and 21.