-
Cell Metabolism Feb 2023Obesity is a considerable health concern with limited pharmacotherapy options of low efficacy. Here, we develop a GLP-1/GDF15 fusion protein and explore its...
Obesity is a considerable health concern with limited pharmacotherapy options of low efficacy. Here, we develop a GLP-1/GDF15 fusion protein and explore its weight-lowering potential in animals. The molecule, QL1005, is engineered via fusing GLP-1 and GDF15 analogs by a peptide linker and conjugating it to a fatty acid for time-action extension. In vitro, the potency of QL1005 is superior to the GLP-1 analog semaglutide. In obese mice, QL1005 induces reductions in body weight, food intake, insulin, fasting glucose, and triglycerides. Notably, these metabolic effects come as a result of activities emanating from both GLP-1 and GDF15, in an individual pathway-balanced fashion. In a cynomolgus monkey model of obesity, QL1005 reduces body weight, food intake, insulin, and glucose in a dose-dependent manner with limited incidence of GI side effects. Altogether, this long-acting, dual GLP-1/GDF15 molecule demonstrates the promise of poly-pharmaceutical approaches in metabolic drug discovery and development.
Topics: Animals; Mice; Body Weight; Glucagon-Like Peptide 1; Glucose; Insulin; Macaca fascicularis; Metabolic Diseases; Obesity; Weight Loss; Growth Differentiation Factor 15
PubMed: 36706758
DOI: 10.1016/j.cmet.2023.01.001 -
Cell Metabolism Jan 2022Unimolecular triple incretins, combining the activity of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon (GCG), have...
Unimolecular triple incretins, combining the activity of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon (GCG), have demonstrated reduction in body weight and improved glucose control in rodent models. We developed SAR441255, a synthetic peptide agonist of the GLP-1, GCG, and GIP receptors, structurally based on the exendin-4 sequence. SAR441255 displays high potency with balanced activation of all three target receptors. In animal models, metabolic outcomes were superior to results with a dual GLP-1/GCG receptor agonist. Preclinical in vivo positron emission tomography imaging demonstrated SAR441255 binding to GLP-1 and GCG receptors. In healthy subjects, SAR441255 improved glycemic control during a mixed-meal tolerance test and impacted biomarkers for GCG and GIP receptor activation. Single doses of SAR441255 were well tolerated. The results demonstrate that integrating GIP activity into dual GLP-1 and GCG receptor agonism provides improved effects on weight loss and glycemic control while buffering the diabetogenic risk of chronic GCG receptor agonism.
Topics: Animals; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycemic Control; Humans; Incretins; Peptides; Receptors, Gastrointestinal Hormone; Receptors, Glucagon; Weight Loss
PubMed: 34932984
DOI: 10.1016/j.cmet.2021.12.005 -
Pharmacological Research Apr 2023We discuss models for the activation and desensitization of α7 nicotinic acetylcholine receptors (nAChRs) and the effects of efficacious type II positive allosteric... (Review)
Review
We discuss models for the activation and desensitization of α7 nicotinic acetylcholine receptors (nAChRs) and the effects of efficacious type II positive allosteric modulators (PAMs) that destabilize α7 desensitized states. Type II PAMs such as PNU-120596 can be used to distinguish inactive compounds from silent agonists, compounds that produce little or no channel activation but stabilize the non-conducting conformations associated with desensitization. We discuss the effects of α7 nAChRs in cells of the immune system and their roles in modulating inflammation and pain through what has come to be known as the cholinergic anti-inflammatory system (CAS). Cells controlling CAS do not generate ion channel currents but rather respond to α7 drugs by modulating intracellular signaling pathways analogous to the effects of metabotropic receptors. Metabotropic signaling by α7 receptors appears to be mediated by receptors in nonconducting conformations and can be accomplished by silent agonists. We discuss electrophysiological structure-activity relationships for α7 silent agonists and their use in cell-based and in vivo assays for CAS regulation. We discuss the strongly desensitizing partial agonist GTS-21 and its effectiveness in modulation of CAS. We also review the properties of the silent agonist NS6740, which is remarkably effective at maintaining α7 receptors in PAM-sensitive desensitized states. Most silent agonists bind to sites overlapping those for orthosteric agonists, but some appear to bind to allosteric sites. Finally, we discuss α9* nAChRs and their potential role in CAS, and ligands that will be useful in defining and distinguishing the specific roles of α7 and α9 in CAS.
Topics: alpha7 Nicotinic Acetylcholine Receptor; Allosteric Regulation; Receptors, Nicotinic; Structure-Activity Relationship; Anti-Inflammatory Agents
PubMed: 36940890
DOI: 10.1016/j.phrs.2023.106736 -
Cancers Mar 2021CD40 is expressed on a variety of antigen-presenting cells. Stimulation of CD40 results in inflammation by upregulation of other costimulatory molecules, increased... (Review)
Review
CD40 is expressed on a variety of antigen-presenting cells. Stimulation of CD40 results in inflammation by upregulation of other costimulatory molecules, increased antigen presentation, maturation (licensing) of dendritic cells, and activation of CD8+ T cells. Here we analyzed gene expression data from The Cancer Genome Atlas in melanoma, renal cell carcinoma, and pancreatic adenocarcinoma and found correlations between CD40 and several genes involved in antigen presentation and T cell function, supporting further exploration of CD40 agonists to treat cancer. Agonist CD40 antibodies have induced anti-tumor effects in several tumor models and the effect has been more pronounced when used in combination with other treatments (immune checkpoint inhibition, chemotherapy, and colony-stimulating factor 1 receptor inhibition). The reduction in tumor growth and ability to reprogram the tumor microenvironment in preclinical models lays the foundation for clinical development of agonistic CD40 antibodies (APX005M, ChiLob7/4, ADC-1013, SEA-CD40, selicrelumab, and CDX-1140) that are currently being evaluated in early phase clinical trials. In this article, we focus on CD40 expression and immunity in cancer, agonistic human CD40 antibodies, and their pre-clinical and clinical development. With the broad pro-inflammatory effects of CD40 and its ligand on dendritic cells and macrophages, and downstream B and T cell activation, agonists of this pathway may enhance the anti-tumor activity of other systemic therapies.
PubMed: 33804039
DOI: 10.3390/cancers13061302 -
Nature Communications Sep 2023GPR61 is an orphan GPCR related to biogenic amine receptors. Its association with phenotypes relating to appetite makes it of interest as a druggable target to treat...
GPR61 is an orphan GPCR related to biogenic amine receptors. Its association with phenotypes relating to appetite makes it of interest as a druggable target to treat disorders of metabolism and body weight, such as obesity and cachexia. To date, the lack of structural information or a known biological ligand or tool compound has hindered comprehensive efforts to study GPR61 structure and function. Here, we report a structural characterization of GPR61, in both its active-like complex with heterotrimeric G protein and in its inactive state. Moreover, we report the discovery of a potent and selective small-molecule inverse agonist against GPR61 and structural elucidation of its allosteric binding site and mode of action. These findings offer mechanistic insights into an orphan GPCR while providing both a structural framework and tool compound to support further studies of GPR61 function and modulation.
Topics: Allosteric Site; Appetite; Binding Sites; Drug Inverse Agonism; GTP-Binding Proteins; Humans; Receptors, G-Protein-Coupled
PubMed: 37741852
DOI: 10.1038/s41467-023-41646-3 -
Frontiers in Endocrinology 2021
Topics: Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Hypoglycemic Agents
PubMed: 34630338
DOI: 10.3389/fendo.2021.760153 -
Frontiers in Immunology 2023Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving multiple organs. It is often called "immortal cancer" due to the difficulties in disease... (Review)
Review
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving multiple organs. It is often called "immortal cancer" due to the difficulties in disease treatment. As the cornerstone of immune regulation, the programmed cell death protein 1 (PD-1) has been extensively studied in the context of chronic inflammation due to its ability of regulating immune response and immunosuppression. Recently, more and more studies on rheumatic immune related complications have also focused on PD-1 and proposed that the use of PD-1 agonist could inhibit the activation of lymphocytes and alleviate SLE disease activity. In this review, we summarized the role of PD-1 in SLE, implicating its potential application as a biomarker to predict SLE disease activity; we also proposed that the combination of PD-1 agonist and low-dose IL-2 may have better therapeutic efficacy, shining light on a new direction for developing specific treatment approaches.
Topics: Humans; Inflammation; Interleukin-2; Lupus Erythematosus, Systemic; Programmed Cell Death 1 Receptor
PubMed: 36969198
DOI: 10.3389/fimmu.2023.1111005 -
Pharmacology Research & Perspectives Jun 2020The corticotropin-releasing factor (CRF) receptors represent potential drug targets for the treatment of anxiety, stress, and other disorders. However, it is not known...
The corticotropin-releasing factor (CRF) receptors represent potential drug targets for the treatment of anxiety, stress, and other disorders. However, it is not known if endogenous CRF receptor agonists display biased signaling, how effective CRF receptor antagonists are at blocking different agonists and signaling pathways or how receptor activity-modifying proteins (RAMPs) effect these processes. This study aimed to address this by investigating agonist and antagonist action at CRF and CRF receptors. We used CRF and CRF receptor transfected Cos7 cells to assess the ability of CRF and urocortin (UCN) peptides to activate cAMP, inositol monophosphate (IP ), and extracellular signal-regulated kinase 1/2 signaling and determined the ability of antagonists to block agonist-stimulated cAMP and IP accumulation. The ability of RAMPs to interact with CRF receptors was also examined. At the CRF receptor, CRF and UCN1 activated signaling in the same manner. However, at the CRF receptor, UCN1 and UCN2 displayed similar signaling profiles, whereas CRF and UCN3 displayed bias away from IP accumulation over cAMP. The antagonist potency was dependent on the receptor, agonist, and signaling pathway. CRF and CRF receptors had no effect on RAMP1 or RAMP2 surface expression. The presence of biased agonism and agonist-dependent antagonism at the CRF receptors offers new avenues for developing drugs tailored to activate a specific signaling pathway or block a specific agonist. Our findings suggest that the already complex CRF receptor pharmacology may be underappreciated and requires further investigation.
Topics: Animals; COS Cells; Chlorocebus aethiops; Corticotropin-Releasing Hormone; Cyclic AMP; Drug Development; HEK293 Cells; Humans; Inositol Phosphates; Receptor Activity-Modifying Protein 1; Receptor Activity-Modifying Protein 2; Receptors, Corticotropin-Releasing Hormone; Signal Transduction; Urocortins
PubMed: 32529807
DOI: 10.1002/prp2.595 -
JCI Insight Jan 2023Podocyte injury and loss are key drivers of primary and secondary glomerular diseases, such as focal segmental glomerulosclerosis (FSGS) and diabetic kidney disease...
Podocyte injury and loss are key drivers of primary and secondary glomerular diseases, such as focal segmental glomerulosclerosis (FSGS) and diabetic kidney disease (DKD). We previously demonstrated the renoprotective role of protein S (PS) and its cognate tyrosine-protein kinase receptor, TYRO3, in models of FSGS and DKD and that their signaling exerts antiapoptotic and antiinflammatory effects to confer protection against podocyte loss. Among the 3 TAM receptors (TYRO3, AXL, and MER), only TYRO3 expression is largely restricted to podocytes, and glomerular TYRO3 mRNA expression negatively correlates with human glomerular disease progression. Therefore, we posited that the agonistic PS/TYRO3 signaling could serve as a potential therapeutic approach to attenuate glomerular disease progression. As PS function is not limited to TYRO3-mediated signal transduction but includes its anticoagulant activity, we focused on the development of TYRO3 agonists as an optimal therapeutic approach to glomerular disease. Among the small-molecule TYRO3 agonistic compounds screened, compound 10 (C-10) showed a selective activation of TYRO3 without any effects on AXL or MER. We also confirmed that C-10 directly binds to TYRO3, but not the other receptors. In vivo, C-10 attenuated proteinuria, glomerular injury, and podocyte loss in mouse models of Adriamycin-induced nephropathy and a db/db model of type 2 diabetes. Moreover, these renoprotective effects of C-10 were lost in Tyro3-knockout mice, indicating that C-10 is a selective agonist of TYRO3 activity that mitigates podocyte injury and glomerular disease. Therefore, C-10, a TYRO3 agonist, could be potentially developed as a new therapy for glomerular disease.
Topics: Mice; Animals; Humans; Glomerulosclerosis, Focal Segmental; Diabetes Mellitus, Type 2; Kidney Glomerulus; Podocytes; Mice, Knockout; Carrier Proteins; Disease Progression; Receptor Protein-Tyrosine Kinases
PubMed: 36454644
DOI: 10.1172/jci.insight.165207 -
Nature Communications Jan 2023Follicle stimulating hormone (FSH) is an essential glycoprotein hormone for human reproduction, which functions are mediated by a G protein-coupled receptor, FSHR....
Follicle stimulating hormone (FSH) is an essential glycoprotein hormone for human reproduction, which functions are mediated by a G protein-coupled receptor, FSHR. Aberrant FSH-FSHR signaling causes infertility and ovarian hyperstimulation syndrome. Here we report cryo-EM structures of FSHR in both inactive and active states, with the active structure bound to FSH and an allosteric agonist compound 21 f. The structures of FSHR are similar to other glycoprotein hormone receptors, highlighting a conserved activation mechanism of hormone-induced receptor activation. Compound 21 f formed extensive interactions with the TMD to directly activate FSHR. Importantly, the unique residue H615 in FSHR plays an essential role in determining FSHR selectivity for various allosteric agonists. Together, our structures provide a molecular basis of FSH and small allosteric agonist-mediated FSHR activation, which could inspire the design of FSHR-targeted drugs for the treatment of infertility and controlled ovarian stimulation for in vitro fertilization.
Topics: Female; Humans; Follicle Stimulating Hormone; Hydrocortisone; Infertility; Receptors, FSH
PubMed: 36720854
DOI: 10.1038/s41467-023-36170-3