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.

天然产物（Natural Products，NPs）始终是药物发现领域极为宝贵的资源，而天然产物的外围修饰演化是一种高效的演化策略。本文报道了一种统一的"甲基向酰胺转化"的外围修饰演化策略，以丹参酮IIA（Tanshinone IIA）和隐丹参酮（Cryptotanshinone）为骨架，用于发现NLRP3炎性小体（NLRP3 inflammasome）抑制剂。本研究共设计合成54种化合物，化学信息学分析显示，这些经过演化的天然产物类似物占据了独特的化学空间。生物学评价结果表明，化合物5m可作为NLRP3炎性小体抑制剂，其能够直接结合NLRP3蛋白的NACHT结构域，阻断NLRP3与ASC的相互作用，从而抑制ASC的寡聚化与NLRP3炎性小体的组装。分子动力学模拟（Molecular Dynamics）分析显示，酰胺基团在结合模式中发挥了至关重要的作用。此外，化合物5m在脓毒症和非酒精性脂肪性肝炎（Non-Alcoholic Steatohepatitis，NASH）小鼠模型中展现出治疗功效。综上，本研究方案为天然产物的外围修饰演化提供了全新的研究视角，并发现了一款新型NLRP3炎性小体抑制剂。