NOD-like receptor (NLR) family are a group of inflammasomes formed by innate immune sensors. NLRP3 is a member of NLR family and its aberrant activation is involved in the pathogenesis of a variety of human diseases. CY-09 is a NLRP3 inhibitor that blocks the ATPase activity of the NLRP3 NACHT domain, which is essential for the oligomerization of NLRP3, resulting in the suppression of NLRP3 inflammasome activation. CY-09 shows inhibitory activities against five major cytochrome P450 enzymes 1A2, 2C9, 2C19, 2D6, and 3A4 with IC50 values of 18.9, 8.18, >50, >50, and 26.0 µM, respectively. CY-09 at 1-10 µM dose-dependently inhibited the monosodium urate (MSU), nigericin, ATP-induced caspase-1 activation and IL-1β secretion in LPS-primed BMDMs. Cytosolic LPS-induced noncanonical NLRP3 activation in BMDMs was also inhibited by CY-09 treatment (1-10µM). CY-09 at the doses of 1-10µM effectively suppressed nigericin-induced ASC oligomerization in BMDMs, but showed no effect on nigericin-induced mitochondrial damage and reactive oxygen species production. Treatment with 5-10µM CY-09 in HEK-293T cells inhibited the interaction of Flag–NLRP3 and mCherry–NLRP3, suggesting the inhibitory function of CY-09 on NLRP3 oligomerization. CY-09 inhibited the ATPase activity of purified NLRP3 at doses of 0.1-1µM, and the Kd value between CY-09 and purified GFP-NLRP3 was about 500nM. In a mouse model of cryopyrin-associated autoinflammatory syndrome, treatment of CY-09 (40mg/kg) efficiently suppressed MSU injection-induced IL-1β production and neutrophil influx[1].
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