Department of Medicine , The University of Tennessee Health Science Center , Memphis , Tennessee 38163 , United States.
J Med Chem. 2019 Aug 8;62(15):6925-6940. doi: 10.1021/acs.jmedchem.9b00187. Epub 2019 Jul 24.
The natural product colletoic acid (CA) is a selective inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which primarily converts cortisone to the active glucocorticoid (GC) cortisol. Here, CA's mode of action and its potential as a chemical tool to study intracellular GC signaling in adipogenesis are disclosed. 11β-HSD1 biochemical studies of CA indicated that its functional groups at C-1, C-4, and C-9 were important for enzymatic activity; an X-ray crystal structure of 11β-HSD1 bound to CA at 2.6 Å resolution revealed the nature of those interactions, namely, a close-fitting and favorable interactions between the constrained CA spirocycle and the catalytic triad of 11β-HSD1. Structure-activity relationship studies culminated in the development of a superior CA analogue with improved target engagement. Furthermore, we demonstrate that CA selectively inhibits preadipocyte differentiation through 11β-HSD1 inhibition, suppressing other relevant key drivers of adipogenesis (i.e., PPARγ, PGC-1α), presumably by negatively modulating the glucocorticoid signaling pathway. The combined findings provide an in-depth evaluation of the mode of action of CA and its potential as a tool compound to study adipose tissue and its implications in metabolic syndrome.
天然产物 colletoic 酸（CA）是 11β-羟甾类脱氢酶 1 型（11β-HSD1）的选择性抑制剂，主要将可的松转化为活性糖皮质激素（GC）皮质醇。在这里，揭示了 CA 的作用模式及其作为研究脂肪生成中细胞内 GC 信号的化学工具的潜力。CA 的 11β-HSD1 生化研究表明，其 C-1、C-4 和 C-9 位的功能基团对酶活性很重要；与 CA 结合的 11β-HSD1 的 X 射线晶体结构分辨率为 2.6Å，揭示了这些相互作用的本质，即约束的 CA 螺环与 11β-HSD1 的催化三联体之间的紧密配合和有利相互作用。构效关系研究最终开发出了一种具有改进靶标结合的优越 CA 类似物。此外，我们证明 CA 通过抑制 11β-HSD1 选择性抑制前脂肪细胞分化，抑制脂肪生成的其他相关关键驱动因素（即 PPARγ、PGC-1α），可能通过负调控糖皮质激素信号通路。综合研究结果深入评估了 CA 的作用模式及其作为研究脂肪组织及其在代谢综合征中的意义的工具化合物的潜力。
