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Publication Abstract from PubMed

The natural product colletoic acid (CA) is a selective inhibitor of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-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 is disclosed. 11beta-HSD1 biochemical studies of CA indicated its functional groups at C-1, C-4, and C-9 were important for enzymatic activity; an X-ray crystal structure of 11beta-HSD1 bound to CA at 2.6 A resolution revealed the nature of those interactions, namely a close-fitting and favorable interactions between the constrained CA spirocycle, and the catalytic triad of 11beta-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 11beta-HSD1 inhibition, suppressing other relevant key drivers of adipogenesis (i.e. PPARgamma, PGC-1alpha), 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.

Mechanistic insight on the mode of action of colletoic acid.,Ling T, Miller DJ, Lang W, Griffith E, Rodriguez-Cortes A, El Ayachi I, Palacios G, Min J, Miranda-Carboni GA, Lee RE, Rivas F J Med Chem. 2019 Jul 11. doi: 10.1021/acs.jmedchem.9b00187. PMID:31294974^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.