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Frontiers in Immunology 2023TNFR2 agonists have been investigated as potential therapies for inflammatory diseases due to their ability to activate and expand immunosuppressive CD4+Foxp3+ Treg... (Review)
Review
TNFR2 agonists have been investigated as potential therapies for inflammatory diseases due to their ability to activate and expand immunosuppressive CD4+Foxp3+ Treg cells and myeloid-derived suppressor cells (MDSCs). Despite TNFR2 being predominantly expressed in Treg cells at high levels, activated effector T cells also exhibit a certain degree of TNFR2 expression. Consequently, the role of TNFR2 signaling in coordinating immune or inflammatory responses under different pathological conditions is complex. In this review article, we analyze possible factors that may determine the therapeutic outcomes of TNFR2 agonism, including the levels of TNFR2 expression on different cell types, the biological properties of TNFR2 agonists, and disease status. Based on recent progress in the understanding of TNFR2 biology and the study of TNFR2 agonistic agents, we discuss the future direction of developing TNFR2 agonists as a therapeutic agents.
Topics: Immunosuppressive Agents; Myeloid-Derived Suppressor Cells; Receptors, Tumor Necrosis Factor, Type II; Signal Transduction; T-Lymphocytes, Regulatory
PubMed: 37662935
DOI: 10.3389/fimmu.2023.1209188 -
Indian Journal of Cancer Mar 2022Androgen deprivation therapy (ADT) using gonadotropin-releasing hormone agonist (s) (GnRH-A) remains the backbone of advanced prostate cancer treatment. In this review,... (Review)
Review
Androgen deprivation therapy (ADT) using gonadotropin-releasing hormone agonist (s) (GnRH-A) remains the backbone of advanced prostate cancer treatment. In this review, we assessed the efficacy, safety, and convenience of administration of various GnRH-A. All GnRH-A (goserelin, triptorelin, buserelin, histrelin, and leuprorelin) have comparable potential to suppress testosterone (T) levels (≤50 ng/dL in a month and ≤20 ng/dL in 3 months). However, goserelin has shown better efficacy in maintaining T levels ≤50 ng/dL compared with leuprolide. The incidences of T escape are lower with goserelin and leuprolide than buserelin. Goserelin also has maximum benefit in prostate-specific antigen suppression. In neoadjuvant setting, when only goserelin was used, the 10-year overall survival (OS) rate was 42.6% to 86%. When either goserelin or leuprolide was used, the 10-year OS rate was 62%. As an adjuvant to radical prostatectomy, goserelin had a 10-year survival rate of 87%, and triptorelin had an 8-year survival rate of 84.6%. Goserelin further showed an absolute survival rate of 49% when used as an adjuvant to radiotherapy. The survival rates further improved when GnRH-A are used as combined androgen blockade compared with monotherapy. The frequency and severity of adverse events (hot flushes, fatigue, sexual dysfunction) are comparable among the GnRH-A. Goserelin appears to be the most convenient of all the GnRH-A for administration. Lack of conclusive comparative evidence makes it imperative to have a holistic approach of considering the patient profile and the disease characteristics to select the appropriate GnRH-A for ADT in prostate cancer.
Topics: Androgen Antagonists; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Prostatic Neoplasms
PubMed: 35343198
DOI: 10.4103/ijc.IJC_65_21 -
Chemical & Pharmaceutical Bulletin 2019To develop potent ligands for the vitamin D receptor (VDR), we designed and synthesized a series of vitamin D analogues with and without 22-alkyl substituents. These... (Review)
Review
To develop potent ligands for the vitamin D receptor (VDR), we designed and synthesized a series of vitamin D analogues with and without 22-alkyl substituents. These analogues exhibited agonistic, partial agonistic, or antagonistic activity. To elucidate the mechanism of action of the analogues, we conducted crystal structure analyses of the ligand-binding domain (LBD) of VDR complexed with the analogues. The VDR-LBD/agonist complex exhibited precise interactions, which clearly explained VDR agonism. The VDR-LBD/partial agonist complex showed two conformers (agonist and antagonist binding conformers) in a single crystal, demonstrating that partial agonism could be explained by the sum of the agonistic and antagonistic activities. Antagonist binding to the VDR-LBD structure was elucidated using both crystal structure analysis and in-solution structural analyses with the small-angle X-ray scattering (SAXS)-molecular dynamics (MD) and hydrogen/deuterium exchange coupled with mass spectrometry (HDX-MS) methods. Several antagonist-binding structures were detected. We found that the antagonist binding structures differed depending on the structure of the antagonist itself, and those structures clearly explained the VDR antagonism. Furthermore, the apo VDR-LBD structure without the ligand in the ligand-binding pocket was revealed and found to have an entrance to accommodate the ligand. Thus we elucidated the mechanisms of action of agonists, partial agonists, and antagonists based on structural changes (differences) in the receptor protein induced by ligand binding.
Topics: Binding Sites; Crystallography, X-Ray; Humans; Ligands; Molecular Dynamics Simulation; Protein Conformation, alpha-Helical; Protein Domains; Receptors, Calcitriol; Vitamin D
PubMed: 31257315
DOI: 10.1248/cpb.c19-00131 -
Biophysical Journal May 2021Agonists are evaluated by a concentration-response curve (CRC), with a midpoint (EC) that indicates potency, a high-concentration asymptote that indicates efficacy, and...
Agonists are evaluated by a concentration-response curve (CRC), with a midpoint (EC) that indicates potency, a high-concentration asymptote that indicates efficacy, and a low-concentration asymptote that indicates constitutive activity. A third agonist attribute, efficiency (η), is the fraction of binding energy that is applied to the conformational change that activates the receptor. We show that η can be calculated from EC and the asymptotes of a CRC derived from either single-channel or whole-cell responses. For 20 agonists of skeletal muscle nicotinic receptors, the distribution of η-values is bimodal with population means at 51% (including acetylcholine, nornicotine, and dimethylphenylpiperazinium) and 40% (including epibatidine, varenicline, and cytisine). The value of η is related inversely to the size of the agonist's headgroup, with high- versus low-efficiency ligands having an average volume of 70 vs. 102 Å. Most binding site mutations have only a small effect on acetylcholine efficiency, except for αY190A (35%), αW149A (60%), and those at αG153 (42%). If η is known, the EC and high-concentration asymptote can be calculated from each other. Hence, an entire CRC can be estimated from the response to a single agonist concentration, and efficacy can be estimated from EC of a CRC that has been normalized to 1. Given η, the level of constitutive activity can be estimated from a single CRC.
Topics: Binding Sites; Nicotinic Agonists; Receptors, Nicotinic
PubMed: 33675765
DOI: 10.1016/j.bpj.2021.02.034 -
Virology Jan 2013The cytokine storm is an aggressive immune response characterized by the recruitment of inflammatory leukocytes and exaggerated levels of cytokines and chemokines at the... (Review)
Review
The cytokine storm is an aggressive immune response characterized by the recruitment of inflammatory leukocytes and exaggerated levels of cytokines and chemokines at the site of infection. Here we review evidence that cytokine storm directly contributes to the morbidity and mortality resulting from influenza virus infection and that sphingosine-1-phosphate (S1P) receptor agonists can abort cytokine storms providing significant protection against pathogenic human influenza viral infections. In experiments using murine models and the human pathogenic 2009 influenza viruses, S1P1 receptor agonist alone reduced deaths from influenza virus by over 80% as compared to lesser protection (50%) offered by the antiviral neuraminidase inhibitor oseltamivir. Optimal protection of 96% was achieved by combined therapy with the S1P1 receptor agonist and oseltamivir. The functional mechanism of S1P receptor agonist(s) action and the predominant role played by pulmonary endothelial cells as amplifiers of cytokine storm during influenza infection are described.
Topics: Animals; Cytokines; Drug Synergism; Drug Therapy, Combination; Endothelial Cells; Enzyme Inhibitors; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Lung; Mice; Mycotoxins; Orthomyxoviridae Infections; Oseltamivir; Receptors, Lysosphingolipid; Survival Rate
PubMed: 23217619
DOI: 10.1016/j.virol.2012.09.039 -
Basic & Clinical Pharmacology &... Jun 2020G protein-coupled receptors (GPCRs) constitute the largest family of receptors and membrane proteins in the human genome with ~800 members of which half are olfactory.... (Review)
Review
G protein-coupled receptors (GPCRs) constitute the largest family of receptors and membrane proteins in the human genome with ~800 members of which half are olfactory. GPCRs are activated by a very broad range of endogenous signalling molecules and are involved in a plethora of physiological functions. All GPCRs contain a transmembrane domain, consisting of a bundle of seven α-helices spanning the cell membrane, and forming the majority of the known ortho- or allosteric ligand binding sites. Due to their many physiological functions and the accessible and druggable transmembrane pocket, GPCRs constitute the largest family of drug targets mediating the actions of 34% of currently marketed drugs. GPCRs activate one or more of the four G protein families (G , G , G and G ) and/or ß-arrestin. About a third of the non-olfactory GPCRs are referred to as orphan receptors which means that their endogenous agonist(s) have not yet been found or firmly established. In this MiniReview, we focus on the orphan GPR139 receptor, for which the aromatic amino acids L-Trp and L-Phe as well as ACTH/α-MSH-related peptides have been proposed as endogenous agonists. GPR139 has been reported to activate several G protein pathways of which G is the primary one. The receptor shows the highest expression in the striatum, thalamus, hypothalamus, pituitary and habenula of the human, rat and mouse CNS. We review the surrogate agonists and antagonists that have been published as well as the agonist pharmacophore and binding site. Finally, the putative physiological functions and therapeutic potential are outlined.
Topics: Animals; Brain; Humans; Mice; Nerve Tissue Proteins; Rats; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 31132229
DOI: 10.1111/bcpt.13263 -
Quantitative Measure of Receptor Agonist and Modulator Equi-Response and Equi-Occupancy Selectivity.Scientific Reports Apr 2016G protein-coupled receptors (GPCRs) are an important class of drug targets. Quantitative analysis by global curve fitting of properly designed dose-dependent GPCR...
G protein-coupled receptors (GPCRs) are an important class of drug targets. Quantitative analysis by global curve fitting of properly designed dose-dependent GPCR agonism and allosterism data permits the determination of all affinity and efficacy parameters based on a general operational model. We report here a quantitative and panoramic measure of receptor agonist and modulator equi-response and equi-occupancy selectivity calculated from these parameters. The selectivity values help to differentiate not only one agonist or modulator from another, but on-target from off-target receptor or functional pathway as well. Furthermore, in conjunction with target site free drug concentrations and endogenous agonist tones, the allosterism parameters and selectivity values may be used to predict in vivo efficacy and safety margins.
Topics: Algorithms; Allosteric Regulation; Animals; Drug Design; Humans; Receptors, G-Protein-Coupled; Structure-Activity Relationship
PubMed: 27116909
DOI: 10.1038/srep25158 -
Endocrine Journal Nov 2022The thyrotropin receptor (TSHR) plays critical roles in thyroid growth and function and in the pathogenesis of several thyroid diseases including Graves' hyperthyroidism... (Review)
Review
The thyrotropin receptor (TSHR) plays critical roles in thyroid growth and function and in the pathogenesis of several thyroid diseases including Graves' hyperthyroidism and ophthalmopathy, non-autoimmune hyperthyroidism and thyroid cancer. Several low-molecular weight compounds (LMWCs) and anti-TSHR monoclonal antibodies (mAbs) with receptor antagonistic and inverse agonistic activities have been reported. The former binds to the pocket formed by the receptor transmembrane bundle, and the latter to the extracellular TSH binding site. Both are effective inhibitors of TSH/thyroid stimulating antibody-stimulated cAMP and/or hyaluronic acid production in TSHR-expressing cells. Anti-insulin-like growth factor 1 inhibitors are also found to inhibit TSHR signaling. Each agent has advantages and disadvantages; for example, mAbs have a higher affinity and longer half-life but are more costly than LMWCs. At present, mAbs appear most promising, yet the development of more efficacious LMWCs is desirable. These agents are anticipated to be efficacious not only for the above-mentioned diseases but also for resistance to thyroid hormone and have utility for thyroid cancer radionuclide scintigraphy/therapy as a new theranostic.
Topics: Humans; Antibodies, Monoclonal; Autoantibodies; Hyperthyroidism; Immunoglobulins, Thyroid-Stimulating; Receptors, G-Protein-Coupled; Receptors, Thyrotropin; Thyroid Diseases; Thyroid Neoplasms; Thyrotropin
PubMed: 36171093
DOI: 10.1507/endocrj.EJ22-0391 -
Current Topics in Medicinal Chemistry 2020Despite similar distribution patterns and intracellular events observed in the nociceptin/ orphanin FQ peptide (NOP) receptor and other opioid receptors, NOP receptor... (Review)
Review
Despite similar distribution patterns and intracellular events observed in the nociceptin/ orphanin FQ peptide (NOP) receptor and other opioid receptors, NOP receptor activation displays unique pharmacological profiles. Several researchers have identified a variety of peptide and nonpeptide ligands to determine the functional roles of NOP receptor activation and observed that NOP receptor- related ligands exhibit pain modality-dependent pain processing. Importantly, NOP receptor activation results in anti-nociception and anti-hypersensitivity at the spinal and supraspinal levels regardless of the experimental settings in non-human primates (NHPs). Given that the NOP receptor agonists synergistically enhance mu-opioid peptide (MOP) receptor agonist-induced anti-nociception, it has been hypothesized that dual NOP and MOP receptor agonists may display promising functional properties as analgesics. Accumulating evidence indicates that the mixed NOP/opioid receptor agonists demonstrate favorable functional profiles. In NHP studies, bifunctional NOP/MOP partial agonists (e.g., AT-121, BU08028, and BU10038) exerted potent anti-nociception via NOP and MOP receptor activation; however, dose-limiting adverse effects associated with the MOP receptor activation, including respiratory depression, itch sensation, physical dependence, and abuse liability, were not observed. Moreover, a mixed NOP/opioid receptor agonist, cebranopadol, presented promising outcomes in clinical trials as a novel analgesic. Collectively, the dual agonistic actions on NOP and MOP receptors, with appropriate binding affinities and efficacies, may be a viable strategy to develop innovative and safe analgesics.
Topics: Analgesics, Opioid; Humans; Isoquinolines; Ligands; Naltrexone; Pain; Phenylpropionates; Receptors, Opioid
PubMed: 32384033
DOI: 10.2174/1568026620666200508082615 -
Advances in Cancer Research 2009Breast cancers can be classified into those which express the estrogen (ER) and progesterone (PR) receptors, those with HER-2 amplification, and those without expression... (Review)
Review
Breast cancers can be classified into those which express the estrogen (ER) and progesterone (PR) receptors, those with HER-2 amplification, and those without expression of ER, PR, or amplified HER-2 (referred to as triple-negative or basal-like breast cancer). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) activates apoptosis upon binding to its receptors in many tumor types and the ligand and agonist antibodies are currently being studied in patients in clinical phases I and II trials. Cell line studies suggest that many breast cancer cell lines are very resistant to TRAIL-induced apoptosis. However, recent data suggest that a subset of triple-negative/basal-like breast cancer cells is sensitive to TRAIL as a single agent. In addition, many studies have demonstrated that resistance to TRAIL-mediated apoptosis in breast cancer cells can be overcome by combinations of TRAIL with chemotherapy, radiation, and various targeted agents. This chapter will discuss the current understanding of the mechanisms, which control TRAIL-mediated apoptosis in breast cancer cells. The preclinical data supporting the use of TRAIL ligands and agonistic antibodies alone and in combination in breast cancer will also be discussed.
Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Drug Delivery Systems; Drug Resistance, Neoplasm; Female; Humans; Receptors, TNF-Related Apoptosis-Inducing Ligand; TNF-Related Apoptosis-Inducing Ligand
PubMed: 19854352
DOI: 10.1016/S0065-230X(09)03003-6