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Journal of the American Chemical Society Jun 2023Class B1 G protein-coupled receptors (GPCRs), collectively, respond to a diverse repertoire of extracellular polypeptide agonists and transmit the encoded messages to...
Class B1 G protein-coupled receptors (GPCRs), collectively, respond to a diverse repertoire of extracellular polypeptide agonists and transmit the encoded messages to cytosolic partners. To fulfill these tasks, these highly mobile receptors must interconvert among conformational states in response to agonists. We recently showed that conformational mobility in polypeptide agonists themselves plays a role in activation of one class B1 GPCR, the receptor for glucagon-like peptide-1 (GLP-1). Exchange between helical and nonhelical conformations near the N-termini of agonists bound to the GLP-1R was revealed to be critical for receptor activation. Here, we ask whether agonist conformational mobility plays a role in the activation of a related receptor, the GLP-2R. Using variants of the hormone GLP-2 and the designed clinical agonist glepaglutide (GLE), we find that the GLP-2R is quite tolerant of variations in α-helical propensity near the agonist N-terminus, which contrasts with signaling at the GLP-1R. A fully α-helical conformation of the bound agonist may be sufficient for GLP-2R signal transduction. GLE is a GLP-2R/GLP-1R dual agonist, and the GLE system therefore enables direct comparison of the responses of these two GPCRs to a single set of agonist variants. This comparison supports the conclusion that the GLP-1R and GLP-2R differ in their response to variations in helical propensity near the agonist N-terminus. The data offer a basis for development of new hormone analogues with distinctive and potentially useful activity profiles; for example, one of the GLE analogues is a potent agonist of the GLP-2R but also a potent antagonist of the GLP-1R, a novel form of polypharmacology.
Topics: Glucagon-Like Peptide 1; Glucagon-Like Peptide-2 Receptor; Peptides; Receptors, G-Protein-Coupled; Signal Transduction; Glucagon-Like Peptide-1 Receptor
PubMed: 37235770
DOI: 10.1021/jacs.3c01628 -
Immunologic Research Aug 2021Toll-like receptors 3 (TLR3) have been broadly studied among all TLRs over the last few decades together with its agonists due to their contribution to cancer... (Comparative Study)
Comparative Study Review
Toll-like receptors 3 (TLR3) have been broadly studied among all TLRs over the last few decades together with its agonists due to their contribution to cancer regression. These agonists undeniably have some shared characteristics such as mimicking dsRNA but pathways through which they exhibit antitumor properties are relatively diverse. In this review, three widely studied agonists RGC100, ARNAX, and poly-IC are discussed along with their structural and physiochemical differences including the signaling cascades through which they exert their actions. Comparison has been made to identify the finest agonist with maximum effectivity and the least side effect profile.
Topics: Adjuvants, Immunologic; Animals; Humans; Poly I-C; RNA; Toll-Like Receptor 3
PubMed: 34145551
DOI: 10.1007/s12026-021-09203-6 -
Medicine Jan 2022Toll-like receptors (TLRs), a family of innate pattern-recognition receptors, have been exploited as a target for antitumor strategy. An increasing number of TLR...
BACKGROUND
Toll-like receptors (TLRs), a family of innate pattern-recognition receptors, have been exploited as a target for antitumor strategy. An increasing number of TLR agonists, serving as immunotherapeutics or vaccine adjuvants, were developed. This study aimed at exploring the status and trend of current researches on TLR agonists through bibliometric analysis.
METHODS
Original publications on TLR agonists were collected from the Web of Science Core Collection. Data were analyzed in terms of publication outputs, journals, countries, institutions, authors, co-authorship, co-citation, research hotspots, and evolution trends through VOSviewer and CiteSpace.
RESULTS
A total of 1914 TLR agonists-related articles, published in 612 academic journals between 2000 and 2019, were enrolled in the study. The Journal of Immunology published the most publications, followed by PLoS One and Blood. The USA that is in possession of the largest number of articles and the most extensive cooperators was the most leading country in this field. University of Minnesota ranked the first in terms of paper totality, but its average citations ranking was lower than University of Pennsylvania. Gudkov AV was the most productive author, whose team reported a TLR5 agonist that had radioprotective activity in mouse and primate models in 2008. The paper of Akira Shizuo, professor of Osaka University, was widely cited by international peers. The research trend of TLR agonists has undergone 3 periods: mechanisms of TLR signalings in immunotherapy (2000-2010), discovery of TLR agonists (2011-2014), application, therapeutic evaluation, and drug design of TLR agonists (2015-2019).
CONCLUSION
This study provides investigators a landscape of TLR agonists research from the perspective of bibliometrics.
Topics: Adjuvants, Vaccine; Animals; Bibliometrics; Biomedical Research; Humans; Mice; Neoplasms; Periodicals as Topic; Publications; Toll-Like Receptors
PubMed: 35029915
DOI: 10.1097/MD.0000000000028520 -
The Journal of Pharmacology and... Mar 2021Pharmacodynamic efficacy of drugs to activate their receptors is a key determinant of drug effects, and intermediate-efficacy agonists are often useful clinically...
Pharmacodynamic efficacy of drugs to activate their receptors is a key determinant of drug effects, and intermediate-efficacy agonists are often useful clinically because they retain sufficient efficacy to produce therapeutically desirable effects while minimizing undesirable effects. Molecular mechanisms of efficacy are not well understood, so rational drug design to control efficacy is not yet possible; however, receptor theory predicts that fixed-proportion mixtures of an agonist and antagonist for a given receptor can be adjusted to precisely control net efficacy of the mixture in activating that receptor. Moreover, the agonist proportion required to produce different effects provides a quantitative scale for comparing efficacy requirements across those effects. To test this hypothesis, the present study evaluated effectiveness of fixed-proportion agonist/antagonist mixtures to produce in vitro and in vivo effects mediated by -opioid receptors (MOR) and cannabinoid type 1 receptors (CBR). Mixtures of 1) the MOR agonist fentanyl and antagonist naltrexone and 2) the CBR agonist CP55,940 and antagonist/inverse agonist rimonabant were evaluated in an in vitro assay of ligand-stimulated guanosine 5'--(3-[S]thio)triphosphate binding and an in vivo assay of thermal nociception in mice. For both agonist/antagonist pairs in both assays, increasing agonist proportions produced graded increases in maximal mixture effects, and lower agonist proportions were sufficient to produce in vivo than in vitro effects. These findings support the utility of agonist-antagonist mixtures as a strategy to control net efficacy of receptor activation and to quantify and compare efficacy requirements across a range of in vitro and in vivo endpoints. SIGNIFICANCE STATEMENT: Manipulation of agonist proportion in agonist/antagonist mixtures governs net mixture efficacy at the target receptor. Parameters of agonist/antagonist mixture effects can provide a quantitative metric for comparison of efficacy requirements across a wide range of conditions.
Topics: Analgesics, Opioid; Animals; CHO Cells; Cannabinoids; Cricetulus; Dose-Response Relationship, Drug; Drug Interactions; Male; Mice; Receptor, Cannabinoid, CB1; Receptors, Opioid, mu
PubMed: 33443077
DOI: 10.1124/jpet.120.000349 -
Frontiers in Pharmacology 2019As a library of cannabinoid (CB) derivatives with (-)--cannabidiol (CBD) or (-)--cannabidivarin (CBDV) scaffold, we synthesized nine novel cannabinoids: 2-hydroxyethyl...
As a library of cannabinoid (CB) derivatives with (-)--cannabidiol (CBD) or (-)--cannabidivarin (CBDV) scaffold, we synthesized nine novel cannabinoids: 2-hydroxyethyl cannabidiolate (2-HEC), 2-hydroxypentyl cannabidiolate (2-HPC), 2,3-dihydroxypropyl cannabidiolate (GCBD), cyclohexyl cannabidiolate (CHC), -hexyl-cannabidiolate (HC), 2-(methylsulfonamido)ethyl cannabidiolate (NMSC), 2-hydroxyethyl cannabidivarinolate (2-HECBDV), cyclohexyl cannabidivarinolate (CHCBDV), and -hexyl cannabidivarinolate (HCBDV). Their binding and intrinsic effects at the CB1- and CB2-receptors and the effects on inflammatory signaling cascades were investigated in in vitro and ex vivo cell models. Binding affinity was studied in membranes isolated from CB-receptor-transfected HEK293EBNA cells, intrinsic functional activity in Chinese hamster ovary (CHO) cells, and activation of nuclear factor κB (NF-κB) and nuclear factor of activated T-cells (NFAT) in phorbol 12-myristate 13-acetate (PMA)/ionomycin (IO)-treated Jurkat T-cells. Inhibition of interleukin (IL)-17-induced pro-inflammatory cytokines and chemokines [IL-6, IL-1β, CC-chemokine ligand 2 (CCL2), and tumor necrosis factor (TNF)-α] was studied in RAW264.7 macrophages at the RNA level. Pro-inflammatory cytokine (IL-1β, IL-6, IL-8, and TNF-α) expression and prostaglandin E2 (PGE) expression were investigated at the protein level in lipopolysaccharide (LPS)-treated primary human monocytes. Derivatives with long aliphatic side chains at the ester position at R [HC ()] as well as the ones with polar side chains [2-HECBDV (), NMSC (), and 2-HEC ()] can be selective for CB2-receptors. The CBDV-derivatives HCBDV and CHCBDV demonstrated specific binding at CB1- and CB2-receptors at nanomolar concentrations. 2-HEC, 2-HPC, GCBD, and NMSC were agonists at CB2-receptor and antagonists at CB1-receptor. CHC bound both receptors at submicromolar ranges and was an agonist for these receptors. 2-HECBDV was an agonist at CB2-receptor and an antagonist at the CB1-receptor despite its modest affinity at this receptor (micromolar range). NMSC inhibited NF-κB and NFAT activity, and 2-HEC, 2-HPC, and GCBD dose-dependently inhibited PMA/IO-stimulated NFAT activation. CHC and HC dose-dependently reduced IL-1β and CCL2 messenger RNA (mRNA) expression. NMSC inhibited IL-1β, CCL2, and TNF-α at lower doses. At higher doses, it induced a pronounced increase in IL-6 mRNA. 2-HEC, 2-HPC, and GCBD dose-dependently inhibited LPS-induced IL-1β, TNF-α, and IL-6 synthesis. NMSC further increased LPS-stimulated IL-1β release but inhibited IL-8, TNF-α, and PGE. The CBD- and CBDV-derivatives studied are suitable for targeting CB-receptors. Some may be used as selective CB2 agonists. The length of the aliphatic rest at R of CBD (pentyl) and CBDV (propyl) did not correlate with the binding affinity. Higher polarity at R appeared to favor the agonistic activity at CB2-receptors.
PubMed: 31824305
DOI: 10.3389/fphar.2019.01284 -
Frontiers in Immunology 2020In recent years, the success of immunotherapy targeting immunoregulatory receptors (immune checkpoints) in cancer have generated enthusiastic support to target these... (Review)
Review
In recent years, the success of immunotherapy targeting immunoregulatory receptors (immune checkpoints) in cancer have generated enthusiastic support to target these receptors in a wide range of other immune related diseases. While the overwhelming focus has been on blockade of these inhibitory pathways to augment immunity, agonistic triggering these receptors offers the promise of dampening pathogenic inflammatory responses. V-domain Ig suppressor of T cell activation (VISTA) has emerged as an immunoregulatory receptor with constitutive expression on both the T cell and myeloid compartments, and whose agonistic targeting has proven a unique avenue relative to other checkpoint pathways to suppress pathologies mediated by the innate arm of the immune system. VISTA agonistic targeting profoundly changes the phenotype of human monocytes towards an anti-inflammatory cell state, as highlighted by striking suppression of the canonical markers CD14 and Fcγr3a (CD16), and the almost complete suppression of both the interferon I (IFN-I) and antigen presentation pathways. The insights from these very recent studies highlight the impact of VISTA agonistic targeting of myeloid cells, and its potential therapeutic implications in the settings of hyperinflammatory responses such as cytokine storms, driven by dysregulated immune responses to viral infections (with a focus on COVID-19) and autoimmune diseases. Collectively, these findings suggest that the VISTA pathway plays a conserved, non-redundant role in myeloid cell function.
Topics: Animals; Antigen Presentation; B7 Antigens; CD4-Positive T-Lymphocytes; COVID-19; Cytokine Release Syndrome; GPI-Linked Proteins; Humans; Immunotherapy; Interferon Type I; Lipopolysaccharide Receptors; Lymphocyte Activation; Mice; Myeloid Cells; Receptors, IgG; SARS-CoV-2
PubMed: 33643285
DOI: 10.3389/fimmu.2020.595950 -
Toxicology Jan 2022Human exposure to per- and polyfluoroalkyl substances (PFAS) is ubiquitous, with mixtures of PFAS detected in drinking water, food, household dust, and other exposure... (Comparative Study)
Comparative Study
Human exposure to per- and polyfluoroalkyl substances (PFAS) is ubiquitous, with mixtures of PFAS detected in drinking water, food, household dust, and other exposure sources. Animal toxicity studies and human epidemiology indicate that PFAS may act through shared mechanisms including activation of peroxisome proliferator activated receptor α (PPARα). However, the effect of PFAS mixtures on human relevant molecular initiating events remains an important data gap in the PFAS literature. Here, we tested the ability of modeling approaches to predict the effect of diverse PPARα ligands on receptor activity using Cos7 cells transiently transfected with a full length human PPARα (hPPARα) expression construct and a peroxisome proliferator response element-driven luciferase reporter. Cells were treated for 24 h with two full hPPARα agonists (pemafibrate and GW7647), a full and a partial hPPARα agonist (pemafibrate and mono(2-ethylhexyl) phthalate), or a full hPPARα agonist and a competitive antagonist (pemafibrate and GW6471). Receptor activity was modeled with three additive approaches: effect summation, relative potency factors (RPF), and generalized concentration addition (GCA). While RPF and GCA accurately predicted activity for mixtures of full hPPARα agonists, only GCA predicted activity for full and partial hPPARα agonists and a full agonist and antagonist. We then generated concentration response curves for seven PFAS, which were well-fit with three-parameter Hill functions. The four perfluorinated carboxylic acids (PFCA) tended to act as full hPPARα agonists while the three perfluorinated sulfonic acids (PFSA) tended to act as partial agonists that varied in efficacy between 28-67 % of the full agonist, positive control level. GCA and RPF performed equally well at predicting the effects of mixtures with three PFCAs, but only GCA predicted experimental activity with mixtures of PFSAs and a mixture of PFCAs and PFSAs at ratios found in the general population. We conclude that of the three approaches, GCA most accurately models the effect of PFAS mixtures on hPPARα activity in vitro. Understanding the differences in efficacy with which PFAS activate hPPARα is essential for accurately predicting the effects of PFAS mixtures. As PFAS can activate multiple nuclear receptors, future analyses should examine mixtures effects in intact cells where multiple molecular initiating events contribute to proximate effects and functional changes.
Topics: Animals; COS Cells; Carboxylic Acids; Chlorocebus aethiops; Dose-Response Relationship, Drug; Drug Partial Agonism; Hydrocarbons, Fluorinated; Models, Molecular; Molecular Structure; PPAR alpha; Signal Transduction; Structure-Activity Relationship; Sulfonic Acids
PubMed: 34743024
DOI: 10.1016/j.tox.2021.153024 -
JCI Insight Apr 2020Heart failure (HF) remains a grievous illness with poor prognosis even with optimal care. The apelin receptor (APJ) counteracts the pressor effect of angiotensin II,...
Heart failure (HF) remains a grievous illness with poor prognosis even with optimal care. The apelin receptor (APJ) counteracts the pressor effect of angiotensin II, attenuates ischemic injury, and has the potential to be a novel target to treat HF. Intravenous administration of apelin improves cardiac function acutely in patients with HF. However, its short half-life restricts its use to infusion therapy. To identify a longer acting APJ agonist, we conducted a medicinal chemistry campaign, leading to the discovery of potent small-molecule APJ agonists with comparable activity to apelin by mimicking the C-terminal portion of apelin-13. Acute infusion increased systolic function and reduced systemic vascular resistance in 2 rat models of impaired cardiac function. Similar results were obtained in an anesthetized but not a conscious canine HF model. Chronic oral dosing in a rat myocardial infarction model reduced myocardial collagen content and improved diastolic function to a similar extent as losartan, a RAS antagonist standard-of-care therapy, but lacked additivity with coadministration. Collectively, this work demonstrates the feasibility of developing clinical, viable, potent small-molecule agonists that mimic the endogenous APJ ligand with more favorable drug-like properties and highlights potential limitations for APJ agonism for this indication.
Topics: Animals; Apelin Receptors; Dogs; Drug Discovery; Heart; Heart Failure; Intercellular Signaling Peptides and Proteins; Rats
PubMed: 32208384
DOI: 10.1172/jci.insight.132898 -
Frontiers in Immunology 2020Interleukin-15 (IL-15) is crucial for the proliferation and survival of NK and CD8 T memory cells, and of significant interest in immuno-oncology. Immune cell expansion... (Review)
Review
Interleukin-15 (IL-15) is crucial for the proliferation and survival of NK and CD8 T memory cells, and of significant interest in immuno-oncology. Immune cell expansion requires continuous IL-15 exposure above a threshold concentration for an extended period. However, the short t of IL-15 makes this impossible to achieve after a single injection without a high C and toxicities. The most effective way to deliver IL-15 is continuous intra-venous infusion, but this administration mode is impractical. Efforts have been devoted to developing IL-15 agonists which after a single injection maintain the cytokine in a narrow therapeutic window for a long period. Enigmatically, although the half-life extension technologies used often extend the half-life of a protein to 1 or more weeks, the modified IL-15 agonists studied usually have systemic elimination half-lives of only a few hours and rarely much longer than 1 day. These short half-lives-common to all circulating IL-15 agonists thus far reported-can be explained by a dynamic increase in clearance of the agonists that accompanies target immune cell proliferation. What is needed is an IL-15 agonist that is as effective as continuous intravenous infusion, but with the convenience and acceptance of single injections at 1-week or longer intervals.
Topics: Animals; Half-Life; Humans; Immunologic Factors; Interleukin-15; Protein Stability; Receptors, Interleukin-15
PubMed: 32903632
DOI: 10.3389/fimmu.2020.01813 -
Frontiers in Endocrinology 2021Cholecystokinin is a gastrointestinal peptide hormone with important roles in metabolic physiology and the maintenance of normal nutritional status, as well as potential... (Review)
Review
Cholecystokinin is a gastrointestinal peptide hormone with important roles in metabolic physiology and the maintenance of normal nutritional status, as well as potential roles in the prevention and management of obesity, currently one of the dominant causes of direct or indirect morbidity and mortality. In this review, we discuss the roles of this hormone and its receptors in maintaining nutritional homeostasis, with a particular focus on appetite control. Targeting this action led to the development of full agonists of the type 1 cholecystokinin receptor that have so far failed in clinical trials for obesity. The possible reasons for clinical failure are discussed, along with alternative pharmacologic strategies to target this receptor for prevention and management of obesity, including development of biased agonists and allosteric modulators. Cellular cholesterol is a natural modulator of the type 1 cholecystokinin receptor, with elevated levels disrupting normal stimulus-activity coupling. The molecular basis for this is discussed, along with strategies to overcome this challenge with a corrective positive allosteric modulator. There remains substantial scope for development of drugs to target the type 1 cholecystokinin receptor with these new pharmacologic strategies and such drugs may provide new approaches for treatment of obesity.
Topics: Allosteric Regulation; Animals; Cholecystokinin; Cholesterol; Humans; Obesity; Receptors, Cholecystokinin
PubMed: 34149622
DOI: 10.3389/fendo.2021.684656