Cellular innate immune sensors, such as STING (STIMULATOR OF INTERFERON GENES), have evolved to detect microbial infection of the cell. STING controls the potent cytosolic DNA-stimulated innate immune pathways and is activated by cyclic dinucleotides (CDNs) such as cyclic di-GMP and cyclic-di-AMP secreted by intracellular bacteria following infection. Alternatively, STING can be activated by cyclic GMP-AMP (cGAMP) generated by a cellular cGAMP synthase cGAS (MB21D1) after association with aberrant cytosolic dsDNA species, which can include microbial DNA or self-DNA leaked from the nucleus. Association with CDNs enables STING to activate the production of type I interferon (IFN) and pro-inflammatory cytokines, which facilitate adaptive immunity. The activation of STING is critical for protection against microbial infection and cancer. However, chronic STING activation is a leading cause of autoinflammatory disease such as severe systemic lupus erythematosus (SLE), STING associated vasculopathy with onset in infancy (SAVI) inflammation of the gut, tissue transplant rejection and others. Here, we describe a new generation of novel small STING antagonists that inhibit STING signaling, for evaluation as anti-inflammatory therapeutic agents. The compounds have been generated by STINGINN LLC, based in Miami, in collaboration with the University of Miami School of Medicine, FL.
Public Health Relevance Statement: PROJECT NARRATIVE Stimulation of the immune system has been shown to be a powerful approach for combatting infection and cancer. However, excessive stimulation can lead to autoinflammatory disease. We have found that overstimulation of an immune pathway controlled by a cellular molecule referred to as STING can effectively trigger inflammation. Here, we have generated a new array of STING specific inhibitors that we intend to evaluate as anti-inflammatory drugs.
Project Terms: inhibitor/antagonist ; inhibitor ; Anti-Inflammatory Agents ; Anti-Inflammatories ; Anti-inflammatory ; Antiinflammatories ; Antiinflammatory Agents ; antiinflammatory ; Antibodies ; Bacteria ; Barbering ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Malignant Neoplasms ; Cancers ; Malignant Tumor ; malignancy ; neoplasm/cancer ; Cell division ; Cell Nucleus ; Nucleus ; Cells ; Cell Body ; Clinical Trials ; Cytosol ; Dinucleoside Phosphates ; dinucleotide ; Disease ; Disorder ; DNA ; Deoxyribonucleic Acid ; DNA Damage ; DNA Injury ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Exhibits ; Family ; Graft Rejection ; Transplant Rejection ; Transplantation Rejection ; Cyclic GMP ; Guanosine Cyclic Monophosphate ; cGMP ; Human ; Modern Man ; allergic/immunologic body system ; allergic/immunologic organ system ; Immune system ; Immunologic Sensitization ; Immunologic Stimulation ; Immunological Sensitization ; Immunological Stimulation ; Immunostimulation ; Immunization ; Infection ; Inflammation ; Interferon Type I ; Laboratories ; Pb element ; heavy metal Pb ; heavy metal lead ; Lead ; L monocytogenes ; L. monocytogenes ; Listeria monocytogenes ; Lupus Erythematosus Disseminatus ; SLE ; Systemic Lupus Erythematous ; Systemic Lupus Erythmatosus ; disseminated lupus erythematosus ; systemic lupus erythematosis ; Systemic Lupus Erythematosus ; Mice ; Mice Mammals ; Murine ; Mus ; Genetic Alteration ; Genetic Change ; Genetic defect ; genome mutation ; Mutation ; Nucleic Acids ; Patients ; Cyclicity ; Rhythmicity ; Periodicity ; Production ; Proteins ; Immunological Receptors ; immune receptor ; Immunologic Receptors ; Safety ; medical college ; school of medicine ; medical schools ; Cell Communication and Signaling ; Cell Signaling ; Intracellular Communication and Signaling ; Signal Transduction Systems ; Signaling ; biological signal transduction ; Signal Transduction ; Cell-Mediated Lympholytic Cells ; Cytolytic T-Cell ; Cytotoxic T Cell ; killer T cell ; Cytotoxic T-Lymphocytes ; Gene Transcription ; RNA Expression ; Transcription ; Genetic Transcription ; Universities ; Vascular Disorder ; blood vessel disorder ; vascular dysfunction ; vasculopathy ; Vascular Diseases ; cytokine ; Generations ; Tissue Transplantation ; CSIF ; CSIF-10 ; Cytokine Synthesis Inhibitory Factor ; IL-10 ; IL10 ; IL10A ; Interleukin 10 Precursor ; Interleukin-10 ; base ; sensor ; Chronic ; Chemicals ; Evaluation ; infantile ; infancy ; insight ; Collaborations ; Therapeutic Agents ; Double-Stranded DNA ; dsDNA ; ds-DNA ; Inflammatory ; Immunes ; Immune ; Event ; Host Defense ; drug efficacy ; microbial ; TLR protein ; Toll-Like Receptor Family Gene ; Toll-like receptors ; novel ; disorder model ; Disease model ; Reporting ; Aicardi Goutieres syndrome ; CREE ENCEPHALITIS ; Encephalopathy with intracranial calcification and chronic lymphocytosis of cerebrospinal fluid ; Encephalopathy, familial infantile, with calcification of basal ganglia and chronic cerebrospinal fluid lymphocytosis ; microcephaly-chorioretinopathy syndrome ; pseudotoxoplasmosis syndrome ; Regulation ; Pharmacodynamics ; response ; High Throughput Assay ; high throughput screening ; 3 Prime Repair Exonuclease 1 ; ATR-Interacting Protein ; DKFZp434J0310 ; DRN3 ; Deoxyribonuclease III, DnaQ/MutD (E. coli)-Like ; FLJ12343 ; Trex1 3'-5' exonuclease ; Trex1 exonuclease ; Three Prime Repair Exonuclease 1 ; Molecular Interaction ; Binding ; preventing ; prevent ; small molecule ; Data ; in vivo ; pathway ; Pathway interactions ; design ; designing ; inflammatory disease of the intestine ; gut inflammation ; inflammatory disorder of the intestine ; intestinal autoinflammation ; intestinal inflammation ; efficacy evaluation ; efficacy analysis ; efficacy assessment ; efficacy examination ; evaluate efficacy ; examine efficacy ; pathogen ; mouse model ; murine model ; T cell response ; adaptive immunity ; screening ; phase I trial ; phase 1 trial ; Formulation ; autoinflammatory ; clinical development ; Stimulator of Interferon Genes ; cGAMP STING ; cGAMP-STING ; cGAMP/STING ; cGAS/STING ; innate immune pathways ; STING agonists ;
