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Marine Drugs Feb 2019The nuclear receptors (NRs) RARα, RXRα, PPARα, and PPARγ represent promising pharmacological targets for the treatment of neurodegenerative diseases. In the search...
The nuclear receptors (NRs) RARα, RXRα, PPARα, and PPARγ represent promising pharmacological targets for the treatment of neurodegenerative diseases. In the search for molecules able to simultaneously target all the above-mentioned NRs, we screened an in-house developed molecular database using a ligand-based approach, identifying (-)-Muqubilin (Muq), a cyclic peroxide norterpene from a marine sponge, as a potential hit. The ability of this compound to stably and effectively bind these NRs was assessed by molecular docking and molecular dynamics simulations. Muq recapitulated all the main interactions of a canonical full agonist for RXRα and both PPARα and PPARγ, whereas the binding mode toward RARα showed peculiar features potentially impairing its activity as full agonist. Luciferase assays confirmed that Muq acts as a full agonist for RXRα, PPARα, and PPARγ with an activity in the low- to sub-micromolar range. On the other hand, in the case of RAR, a very weak agonist activity was observed in the micromolar range. Quite surprisingly, we found that Muq is a positive allosteric modulator for RARα, as both luciferase assays and in vivo analysis using a zebrafish transgenic retinoic acid (RA) reporter line showed that co-administration of Muq with RA produced a potent synergistic enhancement of RARα activation and RA signaling.
Topics: Allosteric Regulation; Animals; Animals, Genetically Modified; Drug Synergism; High-Throughput Screening Assays; Humans; Larva; Models, Molecular; Molecular Docking Simulation; PPAR alpha; PPAR gamma; Peroxides; Porifera; Retinoic Acid Receptor alpha; Terpenes; Tretinoin; Zebrafish
PubMed: 30759808
DOI: 10.3390/md17020110 -
Journal of Medicinal Chemistry Jul 2022The diprovocims, a new class of toll-like receptor (TLR) agonists, bear no similarity to prior TLR agonists, act through a well-defined mechanism (TLR1/TLR2 agonist),...
The diprovocims, a new class of toll-like receptor (TLR) agonists, bear no similarity to prior TLR agonists, act through a well-defined mechanism (TLR1/TLR2 agonist), exhibit exquisite structure-activity relationships, and display in vivo adjuvant activity. They possess potent and efficacious agonist activity toward human TLR1/TLR2 but modest agonism toward the murine receptor. A manner by which diprovocims can be functionalized without impacting hTLR1/TLR2 activity is detailed, permitting future linkage to antigenic, targeting, or delivery moieties. Improvements in both potency and its low efficacy in the murine system were also achieved, permitting more effective use in animal models while maintaining the hTLR1/TLR2 activity. The prototypical member diprovocim-X exhibits the excellent potency/efficacy of diprovocim-1 in human cells, displays substantially improved potency/efficacy in mouse macrophages, and serves as an adjuvant in mice when coadministered with a nonimmunogenic antigen, indicating stimulation of the adaptive as well as innate immune response.
Topics: Adaptive Immunity; Adjuvants, Immunologic; Animals; Cyclopropanes; Humans; Mice; Pyrrolidines; Toll-Like Receptor 1; Toll-Like Receptor 2
PubMed: 35767437
DOI: 10.1021/acs.jmedchem.2c00419 -
Nature Communications Nov 2021The hunger hormone ghrelin activates the ghrelin receptor GHSR to stimulate food intake and growth hormone secretion and regulate reward signaling. Acylation of ghrelin...
The hunger hormone ghrelin activates the ghrelin receptor GHSR to stimulate food intake and growth hormone secretion and regulate reward signaling. Acylation of ghrelin at Ser3 is required for its agonistic action on GHSR. Synthetic agonists of GHSR are under clinical evaluation for disorders related to appetite and growth hormone dysregulation. Here, we report high-resolution cryo-EM structures of the GHSR-G signaling complex with ghrelin and the non-peptide agonist ibutamoren as an investigational new drug. Our structures together with mutagenesis data reveal the molecular basis for the binding of ghrelin and ibutamoren. Structural comparison suggests a salt bridge and an aromatic cluster near the agonist-binding pocket as important structural motifs in receptor activation. Notable structural variations of the G and GHSR coupling are observed in our cryo-EM analysis. Our results provide a framework for understanding GHSR signaling and developing new GHSR agonist drugs.
Topics: Ghrelin; Humans; Receptors, Ghrelin; Signal Transduction
PubMed: 34737341
DOI: 10.1038/s41467-021-26735-5 -
Diabetes, Obesity & Metabolism Aug 2018We performed acute and chronic studies in healthy and diet-induced obese animals using mouse-specific or monkey-specific dual GLP-1R/GCGR agonists to investigate their... (Comparative Study)
Comparative Study
Running on mixed fuel-dual agonistic approach of GLP-1 and GCG receptors leads to beneficial impact on body weight and blood glucose control: A comparative study between mice and non-human primates.
AIM
We performed acute and chronic studies in healthy and diet-induced obese animals using mouse-specific or monkey-specific dual GLP-1R/GCGR agonists to investigate their effects on food intake, body weight, blood glucose control and insulin secretion. The selective GLP-1R agonist liraglutide was used as comparator.
METHODS
The mouse-specific dual agonist and liraglutide were tested in lean wild type, GLP-1R knockout and diet-induced obese mice at different doses. A chronic study was performed in DIO mice to investigate the effect on body weight, food consumption and total energy expenditure (TEE) in obese and diabetic monkeys with a focus on body weight and energy intake.
RESULTS
The mouse-specific dual agonist and liraglutide similarly affected glycaemic control. A higher loss in body weight was measured in dual agonist-treated obese mice. The dual agonist significantly enhanced plasma glucose excursion in overnight fed GLP-1R mice, probably reflecting a potent GCGR agonist activity. It increased TEE and enhanced fat and carbohydrate oxidation, while liraglutide produced no effect on TEE. In obese and diabetic monkeys, treatment with the monkey-specific dual agonist reduced total energy intake to 60%-70% of baseline TEI during chronic treatment. A decrease in body weight and significant improvement in glucose tolerance was observed.
CONCLUSIONS
In DIO mice and non-human primates, dual agonists elicited robust glycaemic control, similar to the marketed GLP-1R agonist, while eliciting greater effects on body weight. Results from DIO mice suggest that the increase in TEE is caused not only by increased fat oxidation but also by an increase in carbohydrate oxidation.
Topics: Animals; Animals, Outbred Strains; Appetite Depressants; Body Weight; Diabetes Mellitus, Type 2; Diet, High-Fat; Dose-Response Relationship, Drug; Drug Therapy, Combination; Energy Intake; Energy Metabolism; Female; Glucagon-Like Peptide-1 Receptor; Hyperglycemia; Hypoglycemic Agents; Insulin Secretion; Macaca fascicularis; Male; Mice, Inbred C57BL; Mice, Knockout; Obesity; Random Allocation; Receptors, Glucagon
PubMed: 29938884
DOI: 10.1111/dom.13212 -
Future Cardiology May 2017The PPARs are a subfamily of three ligand-inducible transcription factors, which belong to the superfamily of nuclear hormone receptors. In mammals, the PPAR subfamily... (Review)
Review
The PPARs are a subfamily of three ligand-inducible transcription factors, which belong to the superfamily of nuclear hormone receptors. In mammals, the PPAR subfamily consists of three members: PPAR-α, PPAR-β/δ and PPAR-γ. PPARs control the expression of a large number of genes involved in metabolic homeostasis, lipid, glucose and energy metabolism, adipogenesis and inflammation. PPARs regulate a large number of metabolic pathways that are implicated in the pathogenesis of metabolic diseases such as metabolic syndrome, Type 2 diabetes mellitus, nonalcoholic fatty liver disease and cardiovascular disease. The aim of this review is to provide up-to-date information about the biochemical and metabolic actions of PPAR-β/δ and PPAR-γ, the therapeutic potential of their agonists currently under clinical development and the cardiovascular disease outcome of clinical trials of PPAR-γ agonists, pioglitazone and rosiglitazone.
Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; PPAR delta; PPAR gamma; PPAR-beta; Pioglitazone; Rosiglitazone; Thiazolidinediones
PubMed: 28581362
DOI: 10.2217/fca-2017-0019 -
Virology Journal May 2017PPAR agonists are often used in HBV infected patients with metabolic disorders. However, as liver-enriched transcriptional factors, PPARs would activate HBV replication....
BACKGROUND
PPAR agonists are often used in HBV infected patients with metabolic disorders. However, as liver-enriched transcriptional factors, PPARs would activate HBV replication. Risks exsit in such patients. This study aimed to assess the influence of commonly used synthetic PPAR agonists on hepatitis B virus (HBV) transcription, replication and expression through HBV replicative mouse models, providing information for physicians to make necessary monitoring and therapeutic adjustment when HBV infected patients receive PPAR agonists treatment.
METHODS
The HBV replicative mouse model was established by hydrodynamic injection of HBV replicative plasmid and the mice were divided into four groups and treated daily for 3 days with saline, PPAR pan-agonist (bezafibrate), PPARα agonist (fenofibrate) and PPARγ agonist (rosiglitazone) respectively. Their serum samples were collected for ECLIA analysis of HBsAg and HBeAg and real-time PCR analysis of Serum HBV DNA. The liver samples were collected for DNA (Southern) filter hybridization of HBV replication intermediates, real-time PCR analysis of HBV mRNA and immunohistochemistry (IHC) analysis of hepatic HBcAg. The alternation of viral transcription, replication and expression were compared in these groups.
RESULT
Serum HBsAg, HBeAg and HBV DNA were significantly elevated after PPAR agonist treatment. So did the viral replication intermediates in mouse livers. HBV mRNA was also significantly increased by these PPAR agonists, implying that PPAR agonists activate HBV replication at transcription level. Moreover, hepatic HBcAg expression in mouse livers with PPAR agonist treatment was elevated as well.
CONCLUSION
Our in vivo study proved that synthetic PPAR agonists bezafibrate, fenofibrate and rosiglitazone would increase HBV replication. It suggested that when HBV infected patients were treated with PPARs agonists because of metabolic diseases, HBV viral load should be monitored and regimens may need to be adjusted, an antiviral therapy may be added.
Topics: Animals; Bezafibrate; DNA, Viral; Enzyme Activators; Enzyme-Linked Immunosorbent Assay; Fenofibrate; Hepatitis B Surface Antigens; Hepatitis B e Antigens; Hepatitis B virus; Male; Mice, Inbred BALB C; Models, Animal; Peroxisome Proliferator-Activated Receptors; Polymerase Chain Reaction; Rosiglitazone; Thiazolidinediones; Viral Load; Virus Replication
PubMed: 28545573
DOI: 10.1186/s12985-017-0765-x -
BMC Pregnancy and Childbirth May 2023Viral infections during pregnancy can have deleterious effects on mothers and their offspring. Monocytes participate in the maternal host defense against invading...
BACKGROUND
Viral infections during pregnancy can have deleterious effects on mothers and their offspring. Monocytes participate in the maternal host defense against invading viruses; however, whether pregnancy alters monocyte responses is still under investigation. Herein, we undertook a comprehensive in vitro study of peripheral monocytes to characterize the differences in phenotype and interferon release driven by viral ligands between pregnant and non-pregnant women.
METHODS
Peripheral blood was collected from third-trimester pregnant (n = 20) or non-pregnant (n = 20, controls) women. Peripheral blood mononuclear cells were isolated and exposed to R848 (TLR7/TLR8 agonist), Gardiquimod (TLR7 agonist), Poly(I:C) (HMW) VacciGrade™ (TLR3 agonist), Poly(I:C) (HMW) LyoVec™ (RIG-I/MDA-5 agonist), or ODN2216 (TLR9 agonist) for 24 h. Cells and supernatants were collected for monocyte phenotyping and immunoassays to detect specific interferons, respectively.
RESULTS
The proportions of classical (CD14CD16), intermediate (CD14CD16), non-classical (CD14CD16), and CD14CD16 monocytes were differentially affected between pregnant and non-pregnant women in response to TLR3 stimulation. The proportions of pregnancy-derived monocytes expressing adhesion molecules (Basigin and PSGL-1) or the chemokine receptors CCR5 and CCR2 were diminished in response to TLR7/TLR8 stimulation, while the proportions of CCR5 monocytes were increased. Such differences were found to be primarily driven by TLR8 signaling, rather than TLR7. Moreover, the proportions of monocytes expressing the chemokine receptor CXCR1 were increased during pregnancy in response to poly(I:C) stimulation through TLR3, but not RIG-I/MDA-5. By contrast, pregnancy-specific changes in the monocyte response to TLR9 stimulation were not observed. Notably, the soluble interferon response to viral stimulation by mononuclear cells was not diminished in pregnancy.
CONCLUSIONS
Our data provide insight into the differential responsiveness of pregnancy-derived monocytes to ssRNA and dsRNA, mainly driven by TLR8 and membrane-bound TLR3, which may help to explain the increased susceptibility of pregnant women to adverse outcomes resulting from viral infection as observed during recent and historic pandemics.
Topics: Pregnancy; Humans; Female; Monocytes; Leukocytes, Mononuclear; Lipopolysaccharide Receptors; Toll-Like Receptor 9; Toll-Like Receptor 7; Toll-Like Receptor 8; Toll-Like Receptor 3; Receptors, IgG; Interferons
PubMed: 37149573
DOI: 10.1186/s12884-023-05562-0 -
Reviews in Endocrine & Metabolic... Jun 2022Semaglutide, a glucagon like peptide-1 (GLP-1) receptor agonist, is available as monotherapy in both subcutaneous as well as oral dosage form (first approved oral GLP-1... (Review)
Review
Semaglutide, a glucagon like peptide-1 (GLP-1) receptor agonist, is available as monotherapy in both subcutaneous as well as oral dosage form (first approved oral GLP-1 receptor agonist). It has been approved as a second line treatment option for better glycaemic control in type 2 diabetes and currently under scrutiny for anti-obesity purpose. Semaglutide has been proved to be safe in adults and elderly patients with renal or hepatic disorders demanding no dose modification. Cardiovascular (CV) outcome trials established that it can reduce various CV risk factors in patients with established CV disorders. Semaglutide is well tolerated with no risk of hypoglycaemia in monotherapy but suffers from gastrointestinal adverse effects. A large population affected with COVID-19 infection were diabetic; therefore use of semaglutide in diabetes as well as CV patients would be very much supportive in maintaining health care system during this pandemic situation. Hence, this peptidic drug can be truly considered as a quintessential of GLP-1 agonists for management of type 2 diabetes.
Topics: Aged; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; COVID-19 Drug Treatment
PubMed: 34993760
DOI: 10.1007/s11154-021-09699-1 -
Bioorganic & Medicinal Chemistry Jan 2023PPAR gamma (PPARG) is a ligand activated transcription factor that regulates genes involved in inflammation, bone biology, lipid homeostasis, as well as a master...
PPAR gamma (PPARG) is a ligand activated transcription factor that regulates genes involved in inflammation, bone biology, lipid homeostasis, as well as a master regulator of adipogenesis and a potential lineage driver of luminal bladder cancer. While PPARG agonists lead to transcriptional activation of canonical target genes, inverse agonists have the opposite effect through inducing a transcriptionally repressive complex leading to repression of canonical target gene expression. While many agonists have been described and tested clinically, inverse agonists offer an underexplored avenue to modulate PPARG biology in vivo. Current inverse agonists lack favorable in vivo properties; herein we describe the discovery and characterization of a series of orally bioavailable 4-chloro-6-fluoroisophthalamides as covalent PPARG inverse-agonists, BAY-5516, BAY-5094, and BAY-9683. Structural studies of this series revealed distinct pre- and post-covalent binding positions, which led to the hypothesis that interactions in the pre-covalent conformation are primarily responsible for driving affinity, while interactions in the post-covalent conformation are more responsible for cellular functional effects by enhancing PPARG interactions with its corepressors. The need to simultaneously optimize for two distinct states may partially explain the steep SAR observed. Exquisite selectivity was achieved over related nuclear receptors in the subfamily due in part to a covalent warhead with low reactivity through an SAr mechanism in addition to the specificity gained through covalent binding to a reactive cysteine uniquely positioned within the PPARG LBD. BAY-5516, BAY-5094, and BAY-9683 lead to pharmacodynamic regulation of PPARG target gene expression in vivo comparable to known inverse agonist SR10221 and represent new tools for future in vivo studies to explore their potential utility for treatment of disorders of hyperactivated PPARG including luminal bladder cancer and other disorders.
Topics: Humans; PPAR gamma; Drug Inverse Agonism; PPAR-gamma Agonists; Gene Expression Regulation; Urinary Bladder Neoplasms
PubMed: 36542958
DOI: 10.1016/j.bmc.2022.117130 -
The Journal of Neuroscience : the... Nov 2017In the present study, we used a simultaneous PET-MR experimental design to investigate the effects of functionally different compounds (agonist, partial agonist, and...
In the present study, we used a simultaneous PET-MR experimental design to investigate the effects of functionally different compounds (agonist, partial agonist, and antagonist) on 5-HT receptor (5-HTR) occupancy and the associated hemodynamic responses. In anesthetized male nonhuman primates ( = 3), we used positron emission tomography (PET) imaging with the radioligand [C]AZ10419369 administered as a bolus followed by constant infusion to measure changes in 5-HTR occupancy. Simultaneously, we measured changes in cerebral blood volume (CBV) as a proxy of drug effects on neuronal activity. The 5-HTR partial agonist AZ10419369 elicited a dose-dependent biphasic hemodynamic response that was related to the 5-HTR occupancy. The magnitude of the response was spatially overlapping with high cerebral 5-HTR densities. High doses of AZ10419369 exerted an extracranial tissue vasoconstriction that was comparable to the less blood-brain barrier-permeable 5-HTR agonist sumatriptan. By contrast, injection of the antagonist GR127935 did not elicit significant hemodynamic responses, even at a 5-HTR cerebral occupancy similar to the one obtained with a high dose of AZ10419369. Given the knowledge we have of the 5-HTR and its function and distribution in the brain, the hemodynamic response informs us about the functionality of the given drug: changes in CBV are only produced when the receptor is stimulated by the partial agonist AZ10419369 and not by the antagonist GR127935, consistent with low basal occupancy by endogenous serotonin. We here show that combined simultaneous positron emission tomography and magnetic resonance imaging uniquely enables the assessment of CNS active compounds. We conducted a series of pharmacological interventions to interrogate 5-HT receptor binding and function and determined blood-brain barrier passage of drugs and demonstrate target involvement. Importantly, we show how the spatial and temporal effects on brain hemodynamics provide information about pharmacologically driven downstream CNS drug effects; the brain hemodynamic response shows characteristic dose-related effects that differ depending on agonistic or antagonistic drug characteristics and on local 5-HT receptor density. The technique lends itself to a comprehensive investigation and understanding of drugs' effects in the brain.
Topics: Animals; Brain; Dose-Response Relationship, Drug; Drug Partial Agonism; Macaca mulatta; Magnetic Resonance Imaging; Male; Positron-Emission Tomography; Receptor, Serotonin, 5-HT1B; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists
PubMed: 28972127
DOI: 10.1523/JNEUROSCI.1971-17.2017