Mechanistic Insight on the Mode of Action of Colletoic Acid

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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6925-6940
Number of pages16
JournalJournal of Medicinal Chemistry
Volume62
Issue number15
DOIs
StatePublished - Aug 8 2019

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11-beta-Hydroxysteroid Dehydrogenase Type 1
Glucocorticoids
Adipogenesis
Cortisone
Structure-Activity Relationship
colletoic acid
Biological Products
Action Potentials
Hydrocortisone
Adipose Tissue
X-Rays

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Ling, T., Miller, D. J., Lang, W. H., Griffith, E., Rodriguez-Cortes, A., El Ayachi, I., ... Rivas, F. (2019). Mechanistic Insight on the Mode of Action of Colletoic Acid. Journal of Medicinal Chemistry, 62(15), 6925-6940. https://doi.org/10.1021/acs.jmedchem.9b00187

Mechanistic Insight on the Mode of Action of Colletoic Acid. / Ling, Taotao; Miller, Darcie J.; Lang, Walter H.; Griffith, Elizabeth; Rodriguez-Cortes, Adaris; El Ayachi, Ikbale; Palacios, Gustavo; Min, Jaeki; Miranda-Carboni, Gustavo; Lee, Richard E.; Rivas, Fatima.

In: Journal of Medicinal Chemistry, Vol. 62, No. 15, 08.08.2019, p. 6925-6940.

Research output: Contribution to journalArticle

Ling, T, Miller, DJ, Lang, WH, Griffith, E, Rodriguez-Cortes, A, El Ayachi, I, Palacios, G, Min, J, Miranda-Carboni, G, Lee, RE & Rivas, F 2019, 'Mechanistic Insight on the Mode of Action of Colletoic Acid', Journal of Medicinal Chemistry, vol. 62, no. 15, pp. 6925-6940. https://doi.org/10.1021/acs.jmedchem.9b00187
Ling T, Miller DJ, Lang WH, Griffith E, Rodriguez-Cortes A, El Ayachi I et al. Mechanistic Insight on the Mode of Action of Colletoic Acid. Journal of Medicinal Chemistry. 2019 Aug 8;62(15):6925-6940. https://doi.org/10.1021/acs.jmedchem.9b00187
Ling, Taotao ; Miller, Darcie J. ; Lang, Walter H. ; Griffith, Elizabeth ; Rodriguez-Cortes, Adaris ; El Ayachi, Ikbale ; Palacios, Gustavo ; Min, Jaeki ; Miranda-Carboni, Gustavo ; Lee, Richard E. ; Rivas, Fatima. / Mechanistic Insight on the Mode of Action of Colletoic Acid. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 15. pp. 6925-6940.
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abstract = "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 {\AA} 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.",
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AB - 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.

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