Mechanistic Insight on the Mode of Action of Colletoic Acid

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.