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首页> 外文期刊>Journal of Medicinal Chemistry >Mechanistic Insight on the Mode of Action of Colletoic Acid
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Mechanistic Insight on the Mode of Action of Colletoic Acid

机译：对胶酸作用方式的机械洞察力

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摘要

The natural product colletoic acid (CA) is a selective inhibitor of 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-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. 11 beta-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 11 beta-HSD1 bound to CA at 2.6 angstrom resolution revealed the nature of those interactions, namely, a close-fitting and favorable interactions between the constrained CA spirocycle and the catalytic triad of 11 beta-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 11 beta-HSD1 inhibition, suppressing other relevant key drivers of adipogenesis (i.e., PPAR gamma, PGC-1 alpha), 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.
机译：天然产物Colletocid酸（CA）是11β-羟类脱氢酶型1（11β-HSD1）的选择性抑制剂，其主要将可氢转化为活性糖皮质激素（GC）皮质醇。这里，公开了CA的作用方式及其作为研究脂肪发生中的细胞内GC信号传导的化学工具的潜力。 11β-HSD1 CA的生化研究表明，其在C-1，C-4和C-9处的官能团对于酶活性很重要; 11β-HSD1的X射线晶体结构在2.6埃分辨率下结合到Ca，揭示了这些相互作用的性质，即受约束的Ca螺旋循环和11β-HSD1的催化三合组之间的牢固且良好的相互作用。结构 - 活动关系研究有助于改进目标接合的高级CA模拟的发展。此外，我们证明CA通过11β-HSD1抑制选择性地抑制前脂肪细胞分化，抑制其他相关的脂肪组织（即，PPARγ，PGC-1α）的相关关键驱动器，可能是通过对糖皮质激素信号传导途径产生负面调节。合并的结果提供了对Ca的作用方式及其作为工具化合物的潜力的深入评估，以研究脂肪组织及其在代谢综合征中的影响。

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  • 来源
    《Journal of Medicinal Chemistry》 |2019年第15期|共16页
  • 作者

    Ling Taotao; Miller Darcie J.; Lang Walter H.; Griffith Elizabeth; Rodriguez-Cortes Adaris; El Ayach Ikbale; Palacios Gustavo; Min Jaeki; Miranda-Carbon Gustavo; Lee Richard E.; Rivas Fatima;

  • 作者单位

    St Jude Childrens Res Hosp Dept Chem Biol &

    Therapeut 262 Danny Thomas Pl Memphis TN 38105 USA;

    St Jude Childrens Res Hosp Dept Struct Biol 262 Danny Thomas Pl Memphis TN 38105 USA;

    St Jude Childrens Res Hosp Dept Chem Biol &

    Therapeut 262 Danny Thomas Pl Memphis TN 38105 USA;

    St Jude Childrens Res Hosp Dept Chem Biol &

    Therapeut 262 Danny Thomas Pl Memphis TN 38105 USA;

    St Jude Childrens Res Hosp Dept Chem Biol &

    Therapeut 262 Danny Thomas Pl Memphis TN 38105 USA;

    Univ Tennessee Hlth Sci Ctr Dept Med Memphis TN 38163 USA;

    St Jude Childrens Res Hosp Dept Chem Biol &

    Therapeut 262 Danny Thomas Pl Memphis TN 38105 USA;

    St Jude Childrens Res Hosp Dept Chem Biol &

    Therapeut 262 Danny Thomas Pl Memphis TN 38105 USA;

    Univ Tennessee Hlth Sci Ctr Dept Med Memphis TN 38163 USA;

    St Jude Childrens Res Hosp Dept Chem Biol &

    Therapeut 262 Danny Thomas Pl Memphis TN 38105 USA;

    St Jude Childrens Res Hosp Dept Chem Biol &

    Therapeut 262 Danny Thomas Pl Memphis TN 38105 USA;

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  • 正文语种 eng
  • 中图分类 药学;
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