Limits...
Structure-based drug design targeting the cell membrane receptor GPBAR1: exploiting the bile acid scaffold towards selective agonism.

Di Leva FS, Festa C, Renga B, Sepe V, Novellino E, Fiorucci S, Zampella A, Limongelli V - Sci Rep (2015)

Bottom Line: A number of dual GPBAR1/FXR agonists are known, however their therapeutic use is limited by multiple unwanted effects due to activation of the diverse downstream signals controlled by the two receptors.On the other hand, designing selective GPBAR1 and FXR agonists is challenging since the two proteins share similar structural requisites for ligand binding.The presence of the 3α-NH2 group on the steroidal scaffold is responsible for the selectivity over FXR unveiling unprecedented structural insights into bile acid receptors activity modulation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, I-80131 Naples, Italy.

ABSTRACT
Bile acids can regulate nutrient metabolism through the activation of the cell membrane receptor GPBAR1 and the nuclear receptor FXR. Developing an exogenous control over these receptors represents an attractive strategy for the treatment of enterohepatic and metabolic disorders. A number of dual GPBAR1/FXR agonists are known, however their therapeutic use is limited by multiple unwanted effects due to activation of the diverse downstream signals controlled by the two receptors. On the other hand, designing selective GPBAR1 and FXR agonists is challenging since the two proteins share similar structural requisites for ligand binding. Here, taking advantage of our knowledge of the two targets, we have identified through a rational drug design study a series of amine lithocholic acid derivatives as selective GPBAR1 agonists. The presence of the 3α-NH2 group on the steroidal scaffold is responsible for the selectivity over FXR unveiling unprecedented structural insights into bile acid receptors activity modulation.

No MeSH data available.


Related in: MedlinePlus

Natural and semi-synthetic GPBAR1 and FXR agonists.CDCA and TLCA, endogenous activators of FXR and GPBAR1, respectively. INT-767 and compound 2, potent dual FXR/GPBAR1 agonists and EUDCOH, a selective GPBAR1 agonist.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4645117&req=5

f1: Natural and semi-synthetic GPBAR1 and FXR agonists.CDCA and TLCA, endogenous activators of FXR and GPBAR1, respectively. INT-767 and compound 2, potent dual FXR/GPBAR1 agonists and EUDCOH, a selective GPBAR1 agonist.

Mentions: Bile acids (BAs), the end products of cholesterol metabolism, are amphipathic water-soluble compounds that regulate a variety of cellular functions. In the liver, cholesterol is first converted in primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA), which are in turn transformed by the intestinal microbiota in secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA). The latter derivatives can be finally modified in their glycine and taurine conjugates1. Both primary and secondary BAs take part to nutrients metabolism and cellular homeostasis through regulatory mechanisms that include the BAs interaction with nuclear (NRs) and cell membrane receptors2. Among bile acid NRs is the farnesoid X receptor (FXR) that is highly expressed in liver and in ileum epithelial cells, where it is generally activated by CDCA (Fig. 1)34. Upon ligand binding, FXR forms a heterodimer with the retinoid X receptor (RXR) that binds specific DNA sequences within the promoter regions of target genes. In such a way, FXR ligands regulate the transcription of proteins that control glucose, lipids and bile acid homeostasis56. An example of bile acid cell membrane receptors is instead the G-protein coupled bile acid receptor 1 (GPBAR1, TGR5, M-BAR1)78. The relevance and complexity of this receptor is reflected by its expression in heterogeneous cellular compartments such as gallbladder, liver, intestine, kidney, adipose tissue, skeletal muscle cells and macrophages/monocytes. Among the most potent natural agonists of GPBAR1 is the tauro-conjugated form of LCA, tauro-lithocolic acid (TLCA, 1)78. The activation of this receptor increases intracellular levels of cAMP and protein kinase A functionality, allowing signaling transduction. Responses to GPBAR1 activation are tissue-specific and may include gallbladder relaxation, increased energy expenditure, improved intestinal motility, glucose metabolism and insulin sensitivity1910. The latter two occur through the release of the glucagon-like peptide 1 (GLP-1) by intestinal L cells upon GPBAR1 activation11. Therefore, the exogenous regulation of this receptor represents an attractive strategy to treat severe enterohepatic and metabolic disorders such as nonalcoholic steatohepatitis (NASH), hypercholesterolaemia, hypertriglyceridaemia, and type 2 diabetes mellitus (T2DM)21213.


Structure-based drug design targeting the cell membrane receptor GPBAR1: exploiting the bile acid scaffold towards selective agonism.

Di Leva FS, Festa C, Renga B, Sepe V, Novellino E, Fiorucci S, Zampella A, Limongelli V - Sci Rep (2015)

Natural and semi-synthetic GPBAR1 and FXR agonists.CDCA and TLCA, endogenous activators of FXR and GPBAR1, respectively. INT-767 and compound 2, potent dual FXR/GPBAR1 agonists and EUDCOH, a selective GPBAR1 agonist.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4645117&req=5

f1: Natural and semi-synthetic GPBAR1 and FXR agonists.CDCA and TLCA, endogenous activators of FXR and GPBAR1, respectively. INT-767 and compound 2, potent dual FXR/GPBAR1 agonists and EUDCOH, a selective GPBAR1 agonist.
Mentions: Bile acids (BAs), the end products of cholesterol metabolism, are amphipathic water-soluble compounds that regulate a variety of cellular functions. In the liver, cholesterol is first converted in primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA), which are in turn transformed by the intestinal microbiota in secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA). The latter derivatives can be finally modified in their glycine and taurine conjugates1. Both primary and secondary BAs take part to nutrients metabolism and cellular homeostasis through regulatory mechanisms that include the BAs interaction with nuclear (NRs) and cell membrane receptors2. Among bile acid NRs is the farnesoid X receptor (FXR) that is highly expressed in liver and in ileum epithelial cells, where it is generally activated by CDCA (Fig. 1)34. Upon ligand binding, FXR forms a heterodimer with the retinoid X receptor (RXR) that binds specific DNA sequences within the promoter regions of target genes. In such a way, FXR ligands regulate the transcription of proteins that control glucose, lipids and bile acid homeostasis56. An example of bile acid cell membrane receptors is instead the G-protein coupled bile acid receptor 1 (GPBAR1, TGR5, M-BAR1)78. The relevance and complexity of this receptor is reflected by its expression in heterogeneous cellular compartments such as gallbladder, liver, intestine, kidney, adipose tissue, skeletal muscle cells and macrophages/monocytes. Among the most potent natural agonists of GPBAR1 is the tauro-conjugated form of LCA, tauro-lithocolic acid (TLCA, 1)78. The activation of this receptor increases intracellular levels of cAMP and protein kinase A functionality, allowing signaling transduction. Responses to GPBAR1 activation are tissue-specific and may include gallbladder relaxation, increased energy expenditure, improved intestinal motility, glucose metabolism and insulin sensitivity1910. The latter two occur through the release of the glucagon-like peptide 1 (GLP-1) by intestinal L cells upon GPBAR1 activation11. Therefore, the exogenous regulation of this receptor represents an attractive strategy to treat severe enterohepatic and metabolic disorders such as nonalcoholic steatohepatitis (NASH), hypercholesterolaemia, hypertriglyceridaemia, and type 2 diabetes mellitus (T2DM)21213.

Bottom Line: A number of dual GPBAR1/FXR agonists are known, however their therapeutic use is limited by multiple unwanted effects due to activation of the diverse downstream signals controlled by the two receptors.On the other hand, designing selective GPBAR1 and FXR agonists is challenging since the two proteins share similar structural requisites for ligand binding.The presence of the 3α-NH2 group on the steroidal scaffold is responsible for the selectivity over FXR unveiling unprecedented structural insights into bile acid receptors activity modulation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, I-80131 Naples, Italy.

ABSTRACT
Bile acids can regulate nutrient metabolism through the activation of the cell membrane receptor GPBAR1 and the nuclear receptor FXR. Developing an exogenous control over these receptors represents an attractive strategy for the treatment of enterohepatic and metabolic disorders. A number of dual GPBAR1/FXR agonists are known, however their therapeutic use is limited by multiple unwanted effects due to activation of the diverse downstream signals controlled by the two receptors. On the other hand, designing selective GPBAR1 and FXR agonists is challenging since the two proteins share similar structural requisites for ligand binding. Here, taking advantage of our knowledge of the two targets, we have identified through a rational drug design study a series of amine lithocholic acid derivatives as selective GPBAR1 agonists. The presence of the 3α-NH2 group on the steroidal scaffold is responsible for the selectivity over FXR unveiling unprecedented structural insights into bile acid receptors activity modulation.

No MeSH data available.


Related in: MedlinePlus