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Journal of Medicinal Chemistry Dec 2023The retinoid X receptors (RXRs) are ligand-activated transcription factors involved in, for example, differentiation and apoptosis regulation. Currently used reference...
The retinoid X receptors (RXRs) are ligand-activated transcription factors involved in, for example, differentiation and apoptosis regulation. Currently used reference RXR agonists suffer from insufficient specificity and poor physicochemical properties, and improved tools are needed to capture the unexplored therapeutic potential of RXR. Endogenous vitamin A-derived RXR ligands and the natural product RXR agonist valerenic acid comprise acrylic acid residues with varying substitution patterns to engage the critical ionic contact with the binding site arginine. To mimic and exploit this natural ligand motif, we probed its structural fusion with synthetic RXR modulator scaffolds, which had profound effects on agonist activity and remarkably boosted potency of an oxaprozin-derived RXR agonist chemotype. Bioisosteric replacement of the acrylic acid to overcome its pan-assay interference compounds (PAINS) character enabled the development of a highly optimized RXR agonist chemical probe.
Topics: Receptors, Retinoic Acid; Ligands; Acrylates; Retinoid X Receptors
PubMed: 38064686
DOI: 10.1021/acs.jmedchem.3c01435 -
Proceedings of the National Academy of... Jan 2023Spinal muscular atrophy (SMA) is a severe autosomal recessive neuromuscular disease affecting children and young adults, caused by mutations of the survival motor neuron...
Spinal muscular atrophy (SMA) is a severe autosomal recessive neuromuscular disease affecting children and young adults, caused by mutations of the survival motor neuron 1 gene (). SMA is characterized by the degeneration of spinal alpha motor neurons (αMNs), associated with muscle paralysis and atrophy, as well as other peripheral alterations. Both growth hormone-releasing hormone (GHRH) and its potent agonistic analog, MR-409, exert protective effects on muscle atrophy, cardiomyopathies, ischemic stroke, and inflammation. In this study, we aimed to assess the protective role of MR-409 in SMNΔ7 mice, a widely used model of SMA. Daily subcutaneous treatment with MR-409 (1 or 2 mg/kg), from postnatal day 2 (P2) to euthanization (P12), increased body weight and improved motor behavior in SMA mice, particularly at the highest dose tested. In addition, MR-409 reduced atrophy and ameliorated trophism in quadriceps and gastrocnemius muscles, as determined by an increase in fiber size, as well as upregulation of myogenic genes and inhibition of proteolytic pathways. MR-409 also promoted the maturation of neuromuscular junctions, by reducing multi-innervated endplates and increasing those mono-innervated. Finally, treatment with MR-409 delayed αMN death and blunted neuroinflammation in the spinal cord of SMA mice. In conclusion, the present study demonstrates that MR-409 has protective effects in SMNΔ7 mice, suggesting that GHRH agonists are promising agents for the treatment of SMA, possibly in combination with SMN-dependent strategies.
Topics: Animals; Mice; Atrophy; Disease Models, Animal; Growth Hormone-Releasing Hormone; Motor Neurons; Muscular Atrophy, Spinal; Spinal Cord; Survival of Motor Neuron 1 Protein
PubMed: 36603028
DOI: 10.1073/pnas.2216814120 -
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 -
ACS Nano Mar 2022The generation of specific humoral and cellular immune responses plays a pivotal role in the development of effective vaccines against tumors. Especially the presence of...
The generation of specific humoral and cellular immune responses plays a pivotal role in the development of effective vaccines against tumors. Especially the presence of antigen-specific, cytotoxic T cells influences the outcome of therapeutic cancer vaccinations. Different strategies, ranging from delivering antigen-encoding mRNAs to peptides or full antigens, are accessible but often suffer from insufficient immunogenicity and require immune-boosting adjuvants as well as carrier platforms to ensure stability and adequate retention. Here, we introduce a pH-responsive nanogel platform as a two-component antitumor vaccine that is safe for intravenous application and elicits robust immune responses and . The underlying chemical design allows for straightforward covalent attachment of a model antigen (ovalbumin) and an immune adjuvant (imidazoquinoline-type TLR7/8 agonist) onto the same nanocarrier system. In addition to eliciting antigen-specific T and B cell responses that outperform mixtures of individual components, our two-component nanovaccine leads in prophylactic and therapeutic studies to an antigen-specific growth reduction of different tumors expressing ovalbumin intracellularly or on their surface. Regarding the versatile opportunities for functionalization, our nanogels are promising for the development of highly customized and potent nanovaccines.
Topics: Adjuvants, Immunologic; Animals; Antigens; Cancer Vaccines; Immunity, Cellular; Mice; Mice, Inbred C57BL; Nanogels; Neoplasms; Ovalbumin; Toll-Like Receptor 7; Toll-Like Receptor 8
PubMed: 35103463
DOI: 10.1021/acsnano.1c10709 -
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 -
Journal of Medicinal Chemistry Jan 2023Osteoclasts have an additional demand for cholesterol compared to normal cells. Liver X receptors (LXRs) are famous for regulation of lipid and cholesterol metabolism....
Osteoclasts have an additional demand for cholesterol compared to normal cells. Liver X receptors (LXRs) are famous for regulation of lipid and cholesterol metabolism. Therefore, we propose that the LXR β agonist can regulate the cholesterol balance in osteoclasts to inhibit osteoclast differentiation. Here, we designed and synthesized a novel LXRβ agonist by introduction of the privileged fragments from anti-osteoporosis agents to the spiro[pyrrolidine-3,3'-oxindole] scaffold which is a novel scaffold of LXR agonists in our previous research. As a result, seven LXRβ agonists inhibited osteoclastogenesis with IC values ranging from 0.078 to 0.36 μM. Especially, the most potent LXRβ agonist significantly inhibited RANKL-induced osteoclast differentiation and bone resorption in vitro and in vivo. Furthermore, selectively activated LXRβ to promote intracellular cholesterol exclusion in osteoclasts and reduce extracellular cholesterol uptake and thereby inhibited osteoclast production. This study provides a new strategy to develop LXRβ agonists for osteoporosis.
Topics: Humans; Orphan Nuclear Receptors; Oxindoles; Osteoclasts; Liver X Receptors; Osteoporosis; Pyrrolidines; Cholesterol
PubMed: 36539349
DOI: 10.1021/acs.jmedchem.2c01661 -
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 -
The Journal of Physical Chemistry. B Jan 2023Elucidation of structural determinants is pivotal for structure-based drug discovery. The Farnesoid X receptor (FXR) is a proven target for NASH; however, its full...
Elucidation of structural determinants is pivotal for structure-based drug discovery. The Farnesoid X receptor (FXR) is a proven target for NASH; however, its full agonism causes certain clinical complications. Therefore, partial agonism (PA) appears as a viable alternative for improved therapeutics. Since the agonist and PA both share the same binding site, i.e., ligand-binding pocket (LBP), which is highly dynamic and has synergy with the substrate binding site, the selective designing of PA is challenging. The identification of structural and conformational determinants is critical for PA compared with an agonist. Furthermore, the mechanism by which PA modulates the structural dynamics of FXR at the residue level, a prerequisite for PA designing, is still elusive. Here, by using ∼4.5 μs of MD simulations and residue-wise communication network analysis, we identified the structural regions which are flexible with PA but frozen with an agonist. Also, the network analysis identified the considerable changes between an agonist and PA in biologically essential zones of FXR such as helix H10/H11 and loop L:H11/H12, which lead to the modulation of synergy between LBP and the substrate binding site. Furthermore, the thermodynamic profiling suggested the methionine residues, mainly M, M, and M, seem to be responsible for the recruitment of PA. The other residues I, Y, L, F, Q, and K are also identified, exclusively interacting with PA. This study offers novel structural and mechanistic insights that are critical for FXR targeted drug discovery for PA designing.
Topics: Binding Sites; Drug Discovery; Ligands; Protein Domains; Receptors, Cytoplasmic and Nuclear
PubMed: 36609158
DOI: 10.1021/acs.jpcb.2c06325 -
Chemico-biological Interactions Feb 2022Bisphenol A (BPA) and bisphenol S (BPS) are agonists of hERα receptors and due to BPA regulations in many countries, several substitutes that are close analogs to BPA...
Bisphenol A (BPA) and bisphenol S (BPS) are agonists of hERα receptors and due to BPA regulations in many countries, several substitutes that are close analogs to BPA and BPS were developed. In the presented study, we have determined human estrogen receptor (hER)α agonist and antagonist activities with the validated OECD assay with the hERα-Hela9903 cell line for five different chemical classes of BPA and BPS analogs. This study also defined clear structure-activity relationships for agonist and antagonist activities of the 12 bisphenols on hERα, which are supported by molecular docking studies. These data show that classical analogs of BPA (e.g., bisphenols B, C, AP, E) have comparable or superior estrogenic agonist potencies compared to BPA and BPS. The most potent of these hERα agonists were even more potent than BPA, as bisphenol B and C, with IC values of 0.31 μM and 0.48 μM, respectively. Among these selected bisphenols, 4-4'-methylenebis (oxyethylenethio)diphenol was the most potent hERα antagonist, with an IC of 0.39 μM. The estrogenic agonist and antagonist potencies of these different chemical classes of BPA and BPS analogs are mutually comparable and can be used as a basis for further structure-activity relationships studies and human risk assessment.
Topics: Benzhydryl Compounds; Phenols
PubMed: 35077665
DOI: 10.1016/j.cbi.2022.109820