Chemistry and Pharmacology of GPBAR1 and FXR Selective Agonists, Dual Agonists, and Antagonists

Marino, Simona De; Festa, Carmen; Sepe, Valentina; Zampella, Angela

doi:10.1007/164_2019_237

Cited by 31 publications

(22 citation statements)

References 132 publications

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“…Because the above mentioned triterpenoids have been identified as natural ligands for two bile acid activated receptors, the Farnesoid-X-Receptor (FXR) and G protein Bile Acid Receptor (GPBAR)-1 (Sepe et al, 2015;De Marino et al, 2019;Fiorucci and Distrutti, 2019), we have further investigated whether mammalian ligands of these receptors were also endowed with the ability to bind the above mentioned RBD's pockets. More specifically, oleanolic, betulinic and ursolic acids have been proved to act as selective and potent GPBAR1 agonists (Sato et al, 2007;Genet et al, 2010;Lo et al, 2016), while glycyrrhetinic acid, the major metabolic component of licorice, and its corresponding saponin, glycyrrhizic acid, have been shown to act as dual FXR and GPBAR1 agonists in transactivation assay (Distrutti et al, 2015), also promoting GLP-1 secretion in type 1-like diabetic rats (Wang et al, 2017).…”

Section: Virtual Screening Of the Fda-approved Drug Librarymentioning

confidence: 99%

“…Ursodeoxycholic acid (UDCA), which is a primary bile acid in mice, but a "tertiary" bile acid found in trace in humans, is, along with CDCA, the only bile acid approved for clinical use, and is a weak agonist for GPBAR1 and considered a neutral or weak antagonist toward FXR (Carino et al, 2019). Taking into account the structural similarity and the ability to bind the same receptor systems, we have carried out an in-depth docking analysis of natural bile acids and their semisynthetic derivatives currently available in therapy or under pre-clinical and clinical development (De Marino et al, 2019) and tested them for their ability to bind the above-mentioned pockets in the RBDs of SARS-CoV-2 S protein ( Table 2).…”

Section: Virtual Screening Of the Fda-approved Drug Librarymentioning

confidence: 99%

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Hijacking SARS-CoV-2/ACE2 Receptor Interaction by Natural and Semi-synthetic Steroidal Agents Acting on Functional Pockets on the Receptor Binding Domain

et al. 2020

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The coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by the severe acute respiratory syndrome coronavirus (SARS)-CoV-2. In light of the urgent need to identify novel approaches to be used in the emergency phase, we have embarked on an exploratory campaign aimed at repurposing natural substances and clinically available drugs as potential anti-SARS-CoV2-2 agents by targeting viral proteins. Here we report on a strategy based on the virtual screening of druggable pockets located in the central β-sheet core of the SARS-CoV-2 Spike's protein receptor binding domain (RBD). By combining an in silico approach and molecular in vitro testing we have been able to identify several triterpenoid/steroidal agents that inhibit interaction of the Spike RBD with the carboxypeptidase domain of the Angiotensin Converting Enzyme (ACE2). In detail, we provide evidence that potential binding sites exist in the RBD of the SARS CoV-2 Spike protein and that occupancy of these pockets reduces the ability of the RBD to bind to the ACE2 consensus in vitro. Naturally occurring and clinically available triterpenoids such as glycyrrhetinic and oleanolic acids, as well as primary and secondary bile acids and their amidated derivatives such as glyco-ursodeoxycholic acid and semi-synthetic derivatives such as obeticholic acid reduces the RBD/ACE2 binding. In aggregate, these results might help to define novel approaches to COVID-19 based on SARS-CoV-2 entry inhibitors.

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Section: Virtual Screening Of the Fda-approved Drug Librarymentioning

confidence: 99%

Section: Virtual Screening Of the Fda-approved Drug Librarymentioning

confidence: 99%

Hijacking SARS-CoV-2/ACE2 Receptor Interaction by Natural and Semi-synthetic Steroidal Agents Acting on Functional Pockets on the Receptor Binding Domain

et al. 2020

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“…Because the above mentioned triterpenoids have been identified as natural ligands for two bile acid activated receptors, the Farnesoid-X-Receptor (FXR) and G protein Bile Acid Receptor (GPBAR)-1 (Sepe et al, 2015;De Marino et al, 2019;Fiorucci and Distrutti, 2019), we have further investigated whether mammalian ligands of these receptors were also endowed with the ability to bind to the above mentioned RBD's pockets. More specifically, oleanolic, betulinic and ursolic acid have been proved to act as selective and potent GPBAR1 agonists (Sato et al, 2007;Genet et al, 2010;Lo et al, 2016), while glycyrrhetinic acid, the major metabolic component of licorice, and its corresponding saponin, glycyrrhizic acid, have been shown to act as dual FXR and GPBAR1 agonists in transactivation assay promoting GLP-1 secretion in type 1-like diabetic rats .…”

Section: Virtual Screening Of the Fda-approved Drug Librarymentioning

confidence: 99%

“…Taking into account the structural similarity and the ability to bind the same receptor systems, we have carried out and in-deep docking analysis of natural BA and their semisynthetic derivatives currently available in therapy or under pre-clinical and clinical development (De Marino et al, 2019) and tested them for their ability to bind on the above-mentioned pockets in the RBD's of SARS-CoV-2 S protein (Table 2). As shown in Table 2, natural BA and their semi-synthetic derivatives exhibit higher affinity scores for the pocket 5.…”

Section: Virtual Screening Of the Fda-approved Drug Librarymentioning

confidence: 99%

Hijacking SARS-Cov-2/ACE2 receptor interaction by natural and semi-synthetic steroidal agents acting on functional pockets on receptor binding region

Carino

Moraca

Fiorillo

et al. 2020

Preprint

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The coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by the severe acute respiratory syndrome coronavirus (SARS)-CoV-2. In the light of the urgent need to identify novel approaches to be used in the emergency phase, a largely explored strategy has been the repurpose of clinically available drugs as new antivirals, by targeting different viral proteins. In this paper, we describe a drug repurposing strategy based on a virtual screening of druggable pockets located in the central -sheet core of the SARS-CoV-2 Spike protein RBD supported by in vitro tests identifying several steroidal derivatives as SARS-CoV-2 entry inhibitors. Our results demonstrate that several potential binding sites exist in the SARS CoV-2 S protein, and that the occupancy of these pockets reduces the ability of the S protein RBD to bind to the ACE2 consensus in vitro. In particular, natural occurring and clinically available steroids as glycyrrhetinic and oleanolic acids, as well as the bile acids derivatives glyco-UDCA and obeticholic acid have been shown to be effective in preventing virus entry in the case of low viral load. All together, these results might help to define novel approaches to reduce the viral load by using SARS-CoV-2 entry inhibitors.

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“…To further investigate the role of GPBAR1 in regulating autophagy, fed mice were challenged with BAR501, a potent and selective GPBAR1 agonist. 53 In this set of experiments, wild-type mice were first fasted for a 16 hours period and then allowed to access food for the following 8 hours (refeeding). During the refeeding protocol, half of the mice were administered 30 mg/kg BAR501 in a single dose by gavage.…”

Section: Gpbar1 Agonism Promotes Autophagymentioning

confidence: 99%

The bile acid activated receptors GPBAR1 and FXR exert antagonistic effects on autophagy

et al. 2020

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Autophagy is a highly conserved catabolic process activated by fasting and caloric restriction. FXR, a receptor for primary bile acids, reverses the activity of cAMP‐response element binding protein (CREB) on autophagy‐related genes (Atg)s and terminates autophagy in the fed state. GPBAR1, a receptor for secondary bile acids, exerts its genomic effects via cAMP‐CREB pathway. By genetic and pharmacological approaches, we have obtained evidence that GPBAR1 functions as a positive modulator of autophagy in liver and white adipose tissue (WAT) in fasting. Mechanistically, we found that Gpbar1−/− mice lack the expression of Cyp2c70 a gene essential for generation of muricholic acids which are FXR antagonists, and have an FXR‐biased bile acid pool. Because FXR represses autophagy, Gpbar1−/− mice show a defective regulation of autophagy in fasting. BAR501, a selective GPBAR1 agonist, induces autophagy in fed mice. Defective regulation of autophagy in Gpbar1−/− could be reversed by FXR antagonism, while repression of autophagy by feeding was partially abrogated by FXR gene ablation, and FXR activation repressed Atgs in the fast state. BAR501 reversed the negative regulatory effects of feeding and FXR agonism on autophagy and promoted the recruitment of CREB to a CRE on the LC3 promoter. In mice exposed to chronic high caloric intake, GPBAR1 agonism ameliorated insulin sensitivity and induced Atgs expression in the liver and WAT. In summary, GPBAR1 is required for positive regulation of autophagy in fasting and its ligands reverse the repressive effects exerted on liver and WAT autophagy flow by FXR in fed.

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Chemistry and Pharmacology of GPBAR1 and FXR Selective Agonists, Dual Agonists, and Antagonists

Cited by 31 publications

References 132 publications

Hijacking SARS-CoV-2/ACE2 Receptor Interaction by Natural and Semi-synthetic Steroidal Agents Acting on Functional Pockets on the Receptor Binding Domain

Hijacking SARS-CoV-2/ACE2 Receptor Interaction by Natural and Semi-synthetic Steroidal Agents Acting on Functional Pockets on the Receptor Binding Domain

Hijacking SARS-Cov-2/ACE2 receptor interaction by natural and semi-synthetic steroidal agents acting on functional pockets on receptor binding region

The bile acid activated receptors GPBAR1 and FXR exert antagonistic effects on autophagy

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