Design, Synthesis, and Bioevaluation of Novel NLRP3 Inhibitor with IBD Immunotherapy from the Virtual Screen

NLRP3,
a crucial member of the NLRP family, plays a pivotal role
in immune regulation and inflammatory modulation. Here, we report
a potent and specific NLRP3 inhibitor Z48 obtained though
docking-based virtual screening and structure–activity relationship
studies with an IC50 of 0.26 μM in THP-1 cells and
0.21 μM in mouse bone marrow-derived macrophages. Mechanistic
studies indicated that Z48 could bind directly to the
NLRP3 protein (KD = 1.05 μM), effectively
blocking the assembly and activation of the NLRP3 inflammasome, consequently
manifesting anti-inflammatory properties. Crucially, with acceptable
mouse pharmacokinetic profiles, Z48 demonstrated notable
therapeutic efficacy in a mouse model of DSS-induced ulcerative colitis,
while displaying no significant therapeutic impact on NLRP3KO mice. In conclusion, this study provided
a promising NLRP3 inflammasome inhibitor with novel molecular scaffold,
poised for further development as a therapeutic candidate in the treatment
of inflammatory bowel disease.