The inflammasomes are protein complexes. The innate immune sensors, including NOD-like receptor (NLR) family members (NLRP1, NLRP3, and NLRC4) as well as other non-NLR receptors form them. Upon activation, the sensor proteins oligomerize and then recruit adaptor protein ASC. It then binds with caspase-1 to form inflammasomes. The assembly of inflammasome results in the cleavage and activation of caspase-1. It then promotes pyroptosis or the maturation and secretion of several proinflammatory cytokines, such as IL-1β or IL-18. NLRP3 can sense many different factors derived from not only pathogen but also environment or host. Thus, the aberrant activation of the NLRP3 inflammasome is an important initiator or promoter in a variety of human complex diseases, including type 2 diabetes and neurodegenerative diseases. CY-09 directly bound to the ATP-binding site of the NLRP3 NACHT domain. Thus, it inhibits its ATPase, oligomerization, and NLRP3 inflammasome activation.
CY-09 directly binds to the ATP-binding motif of the NLRP3 NACHT domain and inhibits NLRP3 ATPase activity, resulting in the suppression of NLRP3 inflammasome assembly and activation.
CY-09 has no effect on LPS-induced priming in bone marrow-derived macrophages (BMDMs). Consistent with the inflammasome inhibition. CY-09 also blocks nigericin-induced BMDM death. CY-09 is a specific inhibitor for the NLRP3 inflammasome. It inhibits inflammasome activation by blocking NLRP3 oligomerization and inflammasome assembly. CY-09 directly binds to NLRP3 and inhibits its ATPase activity. It may bind to the ATP-binding site of NLRP3 and then inhibit NLRP3 ATPase and subsequent NLRP3 oligomerization and activation.
CY-09 reverses metabolic disorders in diabetic mice by inhibition of NLRP3-dependent inflammation. CY-09 not only blocks metabolic stress-induced NLRP3 inflammasome activation but also suppresses NLRP3-dependent metal inflammation. Thus, CY-09 can treat metabolic disorders by inhibition of NLRP3 inflammasome in diabetic mice. CY-09 is active ex vivo for cells from healthy human or gouty patients.
In summary, CY-09 is a selective and direct NLRP3 inhibitor. It will serve as a versatile tool to pharmacologically interrogate NLRP3 biology and study its role in inflammatory diseases.