Peripheral Evolution of Tanshinone IIA and Cryptotanshinone for Discovery of a Potent and Specific NLRP3 Inflammasome Inhibitor

Natural
products (NPs) continue to serve as an invaluable source
in drug discovery, and peripheral evolution of NPs is a highly efficient
evolution strategy. Herein, we describe a unified “methyl to
amide” peripheral evolution of Tanshinone IIA and Cryptotanshinone
for discovery of NLRP3 inflammasome inhibitors. There were 54 compounds
designed and prepared, while the chemoinformatic analysis revealed
that these evolved NP analogues occupy a unique chemical space. Biological
evaluation identified 5m as an NLRP3 inflammasome inhibitor,
and 5m could directly bind to the NACHT domain of the
NLRP3 protein and block the interaction of NLRP3 and ASC, thus suppressing
ASC oligomerization and NLRP3 inflammasome assembly. Molecular dynamic
stimulations revealed that the amide moiety played a vital role in
the binding mode. Moreover, 5m exhibited therapeutical
efficacy in sepsis and the NASH mouse model. In conclusion, this protocol
provides a new vision of NPs’ peripheral evolution and a novel
NLRP3 inflammasome inhibitor.