ABSTRACT
The abnormal activation of signal transducer and activator of transcription (STAT) protein family is recognized as cause or driving force behind multiple diseases progression. Therefore, searching for potential treatment strategy is pursued by multiple scientific groups. We consider that providing comprehensive, integrated and unified dataset for STAT inhibitory compounds may serve as important tool for other researchers. We developed SINBAD (STAT INhbitor Biology And Drug-ability) in response to our experience with inhibitory compound research, knowing that gathering detailed information is crucial for effective experiment design and also for finding potential solutions in case of obtaining inconclusive results. SINBAD is a curated database of STAT inhibitors which have been published and described in scientific articles providing prove of their inhibitory properties. It is a tool allowing easy analysis of experimental conditions and provides detailed information about known STAT inhibitory compounds.
Subject(s)
Intracellular Signaling Peptides and Proteins , Pharmaceutical Preparations , Transcription Factors , Humans , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Signal Transduction , Transcription Factors/antagonists & inhibitorsABSTRACT
Inflammatory processes that recruit leukocytes to injured or infected tissues are crucial for tissue repair and the elimination of pathogens. However, excessive or chronic inflammation promotes tissue damage and disease, as in arthritis, atherosclerosis, inflammatory bowel disease, and COVID-19. Intracellular constituents released from dying cells are among the stimuli that trigger proinflammatory gene expression programs in innate immune cells. We explore how programmed cell death mechanismsapoptosis, necroptosis, and pyroptosismay contribute to inflammatory disease. We discuss inhibition of cell death as a potential therapeutic strategy, focusing on the targets RIPK1 (receptor interacting serine/threonine kinase 1), NLRP3 (NLR family pyrin domain containing 3), and GSDMD (gasdermin D) as important mediators of lytic cell death. We also consider the potential benefits of limiting membrane rupture rather than cell death by targeting NINJ1.
Subject(s)
Apoptosis , Inflammation/physiopathology , Necroptosis , Pyroptosis , Animals , Caspase 8/metabolism , Cell Adhesion Molecules, Neuronal/antagonists & inhibitors , Cell Adhesion Molecules, Neuronal/metabolism , Fas-Associated Death Domain Protein/metabolism , Humans , Inflammasomes/metabolism , Inflammation/drug therapy , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Nerve Growth Factors/antagonists & inhibitors , Nerve Growth Factors/metabolism , Receptor-Interacting Protein Serine-Threonine Kinases/deficiency , Receptor-Interacting Protein Serine-Threonine Kinases/metabolismABSTRACT
The MHC class I-mediated antigen presentation pathway plays a critical role in antiviral immunity. Here we show that the MHC class I pathway is targeted by SARS-CoV-2. Analysis of the gene expression profile from COVID-19 patients as well as SARS-CoV-2 infected epithelial cell lines reveals that the induction of the MHC class I pathway is inhibited by SARS-CoV-2 infection. We show that NLRC5, an MHC class I transactivator, is suppressed both transcriptionally and functionally by the SARS-CoV-2 ORF6 protein, providing a mechanistic link. SARS-CoV-2 ORF6 hampers type II interferon-mediated STAT1 signaling, resulting in diminished upregulation of NLRC5 and IRF1 gene expression. Moreover, SARS-CoV-2 ORF6 inhibits NLRC5 function via blocking karyopherin complex-dependent nuclear import of NLRC5. Collectively, our study uncovers an immune evasion mechanism of SARS-CoV-2 that targets the function of key MHC class I transcriptional regulators, STAT1-IRF1-NLRC5.
Subject(s)
COVID-19/immunology , Genes, MHC Class I/immunology , Interferon Regulatory Factor-1/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , SARS-CoV-2/genetics , STAT1 Transcription Factor/antagonists & inhibitors , Viral Proteins/metabolism , COVID-19/genetics , COVID-19/pathology , COVID-19/virology , Cell Line , Female , Gene Expression Regulation , Humans , Male , Middle Aged , SARS-CoV-2/isolation & purification , Signal Transduction , Viral Proteins/immunologyABSTRACT
Multiple organ dysfunction is the most severe outcome of sepsis progression and is highly correlated with a worse prognosis. Excessive neutrophil extracellular traps (NETs) are critical players in the development of organ failure during sepsis. Therefore, interventions targeting NET release would likely effectively prevent NET-based organ injury associated with this disease. Herein, we demonstrate that the pore-forming protein gasdermin D (GSDMD) is active in neutrophils from septic humans and mice and plays a crucial role in NET release. Inhibition of GSDMD with disulfiram or genic deletion abrogated NET formation, reducing multiple organ dysfunction and sepsis lethality. Mechanistically, we demonstrate that during sepsis, activation of the caspase-11/GSDMD pathway controls NET release by neutrophils during sepsis. In summary, our findings uncover a novel therapeutic use for disulfiram and suggest that GSDMD is a therapeutic target to improve sepsis treatment.
Subject(s)
Extracellular Traps/genetics , Gene Deletion , Intracellular Signaling Peptides and Proteins/genetics , Multiple Organ Failure/genetics , Phosphate-Binding Proteins/genetics , Sepsis/genetics , Acetaldehyde Dehydrogenase Inhibitors/therapeutic use , Adoptive Transfer , Aged , Animals , Cells, Cultured , Disulfiram/therapeutic use , Female , Humans , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Male , Mice, Inbred C57BL , Middle Aged , Multiple Organ Failure/pathology , Multiple Organ Failure/therapy , Phosphate-Binding Proteins/antagonists & inhibitors , Sepsis/pathology , Sepsis/therapyABSTRACT
The novel betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 and caused the coronavirus disease 19 (COVID-19) pandemic due to its high transmissibility and early immunosuppression. Previous studies on other betacoronaviruses suggested that betacoronavirus infection is associated with the host autophagy pathway. However, it is unclear whether any components of autophagy or virophagy can be therapeutic targets for COVID-19 treatment. In this report, we examined the antiviral effect of four well-characterized small molecule inhibitors that target the key cellular factors involved in key steps of the autophagy pathway. They include small molecules targeting the ULK1/Atg1 complex involved in the induction stage of autophagy (ULK1 inhibitor SBI0206965), the ATG14/Beclin1/VPS34 complex involved in the nucleation step of autophagy (class III PI3-kinase inhibitor VPS34-IN1), and a widely-used autophagy inhibitor that persistently inhibits class I and temporary inhibits class III PI3-kinase (3-MA) and a clinically approved autophagy inhibitor that suppresses autophagy by inhibiting lysosomal acidification and prevents the formation of autophagolysosome (HCQ). Surprisingly, not all the tested autophagy inhibitors suppressed SARS-CoV-2 infection. We showed that inhibition of class III PI3-kinase involved in the initiation step of both canonical and noncanonical autophagy potently suppressed SARS-CoV-2 at a nano-molar level. In addition, this specific kinase inhibitor VPS34-IN1, and its bioavailable analogue VVPS34-IN1, potently inhibited SARS-CoV-2 infection in ex vivo human lung tissues. Taken together, class III PI3-kinase may be a possible target for COVID-19 therapeutic development.
Subject(s)
Antiviral Agents/pharmacology , Autophagy/drug effects , COVID-19 Drug Treatment , Class III Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Lung , Protein Kinase Inhibitors/pharmacology , Adaptor Proteins, Vesicular Transport/antagonists & inhibitors , Animals , Autophagy-Related Protein-1 Homolog/antagonists & inhibitors , Autophagy-Related Proteins/antagonists & inhibitors , Chlorocebus aethiops , Drug Repositioning , Humans , In Vitro Techniques , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Lung/drug effects , Lung/pathology , Lung/virology , Vero CellsSubject(s)
Azetidines , COVID-19 Drug Treatment , COVID-19 , Purines , Pyrazoles , SARS-CoV-2/drug effects , Sulfonamides , Antiviral Agents/immunology , Antiviral Agents/pharmacology , Azetidines/immunology , Azetidines/pharmacology , COVID-19/immunology , Clinical Trials as Topic , Humans , Immunologic Factors/pharmacology , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Janus Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Purines/immunology , Purines/pharmacology , Pyrazoles/immunology , Pyrazoles/pharmacology , Sulfonamides/immunology , Sulfonamides/pharmacology , Treatment OutcomeSubject(s)
Antiviral Agents/therapeutic use , COVID-19 Drug Treatment , Clomiphene/therapeutic use , SARS-CoV-2/drug effects , Selective Estrogen Receptor Modulators/therapeutic use , Virus Internalization/drug effects , Antiviral Agents/pharmacology , COVID-19/epidemiology , Clomiphene/pharmacology , Drug Repositioning , Ebolavirus/drug effects , Endosomes/drug effects , Humans , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Lysosomes/drug effects , Models, Biological , Niemann-Pick C1 Protein , Pandemics , SARS-CoV-2/physiology , Selective Estrogen Receptor Modulators/pharmacologyABSTRACT
Baricitinib is an oral Janus kinase (JAK)1/JAK2 inhibitor approved for the treatment of rheumatoid arthritis (RA) that was independently predicted, using artificial intelligence (AI) algorithms, to be useful for COVID-19 infection via proposed anti-cytokine effects and as an inhibitor of host cell viral propagation. We evaluated the in vitro pharmacology of baricitinib across relevant leukocyte subpopulations coupled to its in vivo pharmacokinetics and showed it inhibited signaling of cytokines implicated in COVID-19 infection. We validated the AI-predicted biochemical inhibitory effects of baricitinib on human numb-associated kinase (hNAK) members measuring nanomolar affinities for AAK1, BIKE, and GAK. Inhibition of NAKs led to reduced viral infectivity with baricitinib using human primary liver spheroids. These effects occurred at exposure levels seen clinically. In a case series of patients with bilateral COVID-19 pneumonia, baricitinib treatment was associated with clinical and radiologic recovery, a rapid decline in SARS-CoV-2 viral load, inflammatory markers, and IL-6 levels. Collectively, these data support further evaluation of the anti-cytokine and anti-viral activity of baricitinib and support its assessment in randomized trials in hospitalized COVID-19 patients.
Subject(s)
Antiviral Agents/pharmacology , Artificial Intelligence , Azetidines/pharmacology , Betacoronavirus , Coronavirus Infections/drug therapy , Pandemics , Pneumonia, Viral/drug therapy , Protein Kinase Inhibitors/therapeutic use , Sulfonamides/pharmacology , Adult , Aged , Antiviral Agents/pharmacokinetics , Antiviral Agents/therapeutic use , Azetidines/pharmacokinetics , Azetidines/therapeutic use , COVID-19 , Cytokines/antagonists & inhibitors , Drug Evaluation, Preclinical , Drug Repositioning , Female , Humans , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Leukocytes/drug effects , Liver , Male , Middle Aged , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Purines , Pyrazoles , SARS-CoV-2 , Spheroids, Cellular/drug effects , Spheroids, Cellular/virology , Sulfonamides/pharmacokinetics , Sulfonamides/therapeutic use , COVID-19 Drug TreatmentABSTRACT
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has resulted in the death of more than 328,000 persons worldwide in the first 5 months of 2020. Herculean efforts to rapidly design and produce vaccines and other antiviral interventions are ongoing. However, newly evolving viral mutations, the prospect of only temporary immunity, and a long path to regulatory approval pose significant challenges and call for a common, readily available, and inexpensive treatment. Strategic drug repurposing combined with rapid testing of established molecular targets could provide a pause in disease progression. SARS-CoV-2 shares extensive structural and functional conservation with SARS-CoV-1, including engagement of the same host cell receptor (angiotensin-converting enzyme 2) localized in cholesterol-rich microdomains. These lipid-enveloped viruses encounter the endosomal/lysosomal host compartment in a critical step of infection and maturation. Niemann-Pick type C (NP-C) disease is a rare monogenic neurodegenerative disease caused by deficient efflux of lipids from the late endosome/lysosome (LE/L). The NP-C disease-causing gene (NPC1) has been strongly associated with viral infection, both as a filovirus receptor (e.g., Ebola) and through LE/L lipid trafficking. This suggests that NPC1 inhibitors or NP-C disease mimetics could serve as anti-SARS-CoV-2 agents. Fortunately, there are such clinically approved molecules that elicit antiviral activity in preclinical studies, without causing NP-C disease. Inhibition of NPC1 may impair viral SARS-CoV-2 infectivity via several lipid-dependent mechanisms, which disturb the microenvironment optimum for viral infectivity. We suggest that known mechanistic information on NPC1 could be utilized to identify existing and future drugs to treat COVID-19.
Subject(s)
Anticholesteremic Agents/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Intracellular Signaling Peptides and Proteins/genetics , Niemann-Pick Disease, Type C/drug therapy , Pandemics , Pneumonia, Viral/drug therapy , Androstenes/therapeutic use , Angiotensin-Converting Enzyme 2 , Betacoronavirus/metabolism , Betacoronavirus/pathogenicity , COVID-19 , Cholesterol/metabolism , Coronavirus Infections/diagnosis , Coronavirus Infections/epidemiology , Drug Repositioning/methods , Humans , Hydroxychloroquine/therapeutic use , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/metabolism , Lysosomes/drug effects , Lysosomes/metabolism , Lysosomes/virology , Niemann-Pick C1 Protein , Niemann-Pick Disease, Type C/genetics , Niemann-Pick Disease, Type C/metabolism , Niemann-Pick Disease, Type C/pathology , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/diagnosis , Pneumonia, Viral/epidemiology , Protein Binding , Receptors, Virus/antagonists & inhibitors , Receptors, Virus/genetics , Receptors, Virus/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolismABSTRACT
Drug repurposing is potentially the fastest available option in the race to identify safe and efficacious drugs that can be used to prevent and/or treat COVID-19. By describing the life cycle of the newly emergent coronavirus, SARS-CoV-2, in light of emerging data on the therapeutic efficacy of various repurposed antimicrobials undergoing testing against the virus, we highlight in this review a possible mechanistic convergence between some of these tested compounds. Specifically, we propose that the lysosomotropic effects of hydroxychloroquine and several other drugs undergoing testing may be responsible for their demonstrated in vitro antiviral activities against COVID-19. Moreover, we propose that Niemann-Pick disease type C (NPC), a lysosomal storage disorder, may provide new insights into potential future therapeutic targets for SARS-CoV-2, by highlighting key established features of the disorder that together result in an "unfavorable" host cellular environment that may interfere with viral propagation. Our reasoning evolves from previous biochemical and cell biology findings related to NPC, coupled with the rapidly evolving data on COVID-19. Our overall aim is to suggest that pharmacological interventions targeting lysosomal function in general, and those particularly capable of reversibly inducing transient NPC-like cellular and biochemical phenotypes, constitute plausible mechanisms that could be used to therapeutically target COVID-19.