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1.
JCI Insight ; 7(11)2022 06 08.
Article in English | MEDLINE | ID: covidwho-1807764

ABSTRACT

COVID-19 infection causes collapse of glomerular capillaries and loss of podocytes, culminating in a severe kidney disease called COVID-19-associated nephropathy (COVAN). The underlying mechanism of COVAN is unknown. We hypothesized that cytokines induced by COVID-19 trigger expression of pathogenic APOL1 via JAK/STAT signaling, resulting in podocyte loss and COVAN phenotype. Here, based on 9 biopsy-proven COVAN cases, we demonstrated for the first time, to the best of our knowledge, that APOL1 protein was abundantly expressed in podocytes and glomerular endothelial cells (GECs) of COVAN kidneys but not in controls. Moreover, a majority of patients with COVAN carried 2 APOL1 risk alleles. We show that recombinant cytokines induced by SARS-CoV-2 acted synergistically to drive APOL1 expression through the JAK/STAT pathway in primary human podocytes, GECs, and kidney micro-organoids derived from a carrier of 2 APOL1 risk alleles, but expression was blocked by a JAK1/2 inhibitor, baricitinib. We demonstrate that cytokine-induced JAK/STAT/APOL1 signaling reduced the viability of kidney organoid podocytes but was rescued by baricitinib. Together, our results support the conclusion that COVID-19-induced cytokines are sufficient to drive COVAN-associated podocytopathy via JAK/STAT/APOL1 signaling and that JAK inhibitors could block this pathogenic process. These findings suggest JAK inhibitors may have therapeutic benefits for managing cytokine-induced, APOL1-mediated podocytopathy.


Subject(s)
COVID-19 , Cytokines , Janus Kinase Inhibitors , Kidney Diseases , Apolipoprotein L1/genetics , Azetidines/pharmacology , COVID-19/drug therapy , COVID-19/metabolism , Cytokines/metabolism , Endothelial Cells/metabolism , Humans , Janus Kinase Inhibitors/pharmacology , Janus Kinases/metabolism , Kidney Diseases/drug therapy , Kidney Diseases/metabolism , Kidney Diseases/virology , Organoids/metabolism , Purines/pharmacology , Pyrazoles/pharmacology , SARS-CoV-2/isolation & purification , STAT Transcription Factors/metabolism , Signal Transduction/drug effects , Sulfonamides/pharmacology
2.
Mol Cell Biochem ; 477(3): 711-726, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1616202

ABSTRACT

The novel coronavirus pandemic has emerged as one of the significant medical-health challenges of the current century. The World Health Organization has named this new virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the first detection of SARS-CoV-2 in November 2019 in Wuhan, China, physicians, researchers, and others have made it their top priority to find drugs and cures that can effectively treat patients and reduce mortality rates. The symptoms of Coronavirus Disease 2019 (COVID-19) include fever, dry cough, body aches, and anosmia. Various therapeutic compounds have been investigated and applied to mitigate the symptoms in COVID-19 patients and cure the disease. Degenerative virus analyses of the infection incidence and COVID-19 have demonstrated that SARS-CoV-2 penetrates the pulmonary alveoli's endothelial cells through Angiotensin-Converting Enzyme 2 (ACE2) receptors on the membrane, stimulates various signaling pathways and causes excessive secretion of cytokines. The continuous triggering of the innate and acquired immune system, as well as the overproduction of pro-inflammatory factors, cause a severe condition in the COVID-19 patients, which is called "cytokine storm". It can lead to acute respiratory distress syndrome (ARDS) in critical patients. Severe and critical COVID-19 cases demand oxygen therapy and mechanical ventilator support. Various drugs, including immunomodulatory and immunosuppressive agents (e.g., monoclonal antibodies (mAbs) and interleukin antagonists) have been utilized in clinical trials. However, the studies and clinical trials have documented diverging findings, which seem to be due to the differences in these drugs' possible mechanisms of action. These drugs' mechanism of action generally includes suppressing or modulating the immune system, preventing the development of cytokine storm via various signaling pathways, and enhancing the blood vessels' diameter in the lungs. In this review article, multiple medications from different drug families are discussed, and their possible mechanisms of action are also described.


Subject(s)
Antiviral Agents/immunology , COVID-19/drug therapy , Immunomodulating Agents/pharmacology , Antibodies, Monoclonal, Humanized/immunology , Antibodies, Monoclonal, Humanized/pharmacology , Antiviral Agents/pharmacology , Azetidines/immunology , Azetidines/pharmacology , COVID-19/etiology , Dexamethasone/immunology , Dexamethasone/pharmacology , Famotidine/immunology , Famotidine/pharmacology , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/immunology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Infliximab/immunology , Infliximab/pharmacology , Interleukin 1 Receptor Antagonist Protein/immunology , Interleukin 1 Receptor Antagonist Protein/pharmacology , Melatonin/immunology , Melatonin/pharmacology , Purines/immunology , Purines/pharmacology , Pyrazoles/immunology , Pyrazoles/pharmacology , Sulfonamides/immunology , Sulfonamides/pharmacology
3.
Sci Adv ; 7(1)2021 01.
Article in English | MEDLINE | ID: covidwho-1388432

ABSTRACT

Using AI, we identified baricitinib as having antiviral and anticytokine efficacy. We now show a 71% (95% CI 0.15 to 0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age, 81 years). An additional 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-α2 increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by greater than fivefold. RNA-seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and superresolution microscopy, we found that baricitinib exerts activity rapidly through the inhibition of host proteins (numb-associated kinases), uniquely among antivirals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication, and the cytokine storm and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivize further randomized controlled trials.


Subject(s)
Antiviral Agents/pharmacology , Azetidines/pharmacology , COVID-19/mortality , Enzyme Inhibitors/pharmacology , Janus Kinases/antagonists & inhibitors , Liver/virology , Purines/pharmacology , Pyrazoles/pharmacology , SARS-CoV-2/pathogenicity , Sulfonamides/pharmacology , Adult , Aged , Aged, 80 and over , COVID-19/drug therapy , COVID-19/metabolism , COVID-19/virology , Cytokine Release Syndrome , Cytokines/metabolism , Drug Evaluation, Preclinical , Female , Gene Expression Profiling , Humans , Interferon alpha-2/metabolism , Italy , Janus Kinases/metabolism , Liver/drug effects , Male , Middle Aged , Patient Safety , Platelet Activation , Proportional Hazards Models , RNA-Seq , Spain , Virus Internalization/drug effects
4.
Mol Syst Biol ; 17(9): e10426, 2021 09.
Article in English | MEDLINE | ID: covidwho-1355289

ABSTRACT

Although 15-20% of COVID-19 patients experience hyper-inflammation induced by massive cytokine production, cellular triggers of this process and strategies to target them remain poorly understood. Here, we show that the N-terminal domain (NTD) of the SARS-CoV-2 spike protein substantially induces multiple inflammatory molecules in myeloid cells and human PBMCs. Using a combination of phenotypic screening with machine learning-based modeling, we identified and experimentally validated several protein kinases, including JAK1, EPHA7, IRAK1, MAPK12, and MAP3K8, as essential downstream mediators of NTD-induced cytokine production, implicating the role of multiple signaling pathways in cytokine release. Further, we found several FDA-approved drugs, including ponatinib, and cobimetinib as potent inhibitors of the NTD-mediated cytokine release. Treatment with ponatinib outperforms other drugs, including dexamethasone and baricitinib, inhibiting all cytokines in response to the NTD from SARS-CoV-2 and emerging variants. Finally, ponatinib treatment inhibits lipopolysaccharide-mediated cytokine release in myeloid cells in vitro and lung inflammation mouse model. Together, we propose that agents targeting multiple kinases required for SARS-CoV-2-mediated cytokine release, such as ponatinib, may represent an attractive therapeutic option for treating moderate to severe COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Cytokines/metabolism , Host-Pathogen Interactions/physiology , Animals , Azetidines/pharmacology , Host-Pathogen Interactions/drug effects , Humans , Imidazoles/pharmacology , Interleukin-1 Receptor-Associated Kinases/metabolism , Janus Kinase 1/metabolism , Lipopolysaccharides/toxicity , Machine Learning , Male , Mice , Mice, Inbred C57BL , Neutrophils/virology , Protein Kinase Inhibitors/pharmacology , Purines/pharmacology , Pyrazoles/pharmacology , Pyridazines/pharmacology , RAW 264.7 Cells , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/metabolism , Sulfonamides/pharmacology
5.
Int J Mol Sci ; 22(15)2021 Jul 27.
Article in English | MEDLINE | ID: covidwho-1332900

ABSTRACT

A novel series of N-substituted cis- and trans-3-aryl-4-(diethoxyphosphoryl)azetidin-2-ones were synthesized by the Kinugasa reaction of N-methyl- or N-benzyl-(diethyoxyphosphoryl)nitrone and selected aryl alkynes. Stereochemistry of diastereoisomeric adducts was established based on vicinal H3-H4 coupling constants in azetidin-2-one ring. All the obtained azetidin-2-ones were evaluated for the antiviral activity against a broad range of DNA and RNA viruses. Azetidin-2-one trans-11f showed moderate inhibitory activity against human coronavirus (229E) with EC50 = 45 µM. The other isomer cis-11f was active against influenza A virus H1N1 subtype (EC50 = 12 µM by visual CPE score; EC50 = 8.3 µM by TMS score; MCC > 100 µM, CC50 = 39.9 µM). Several azetidin-2-ones 10 and 11 were tested for their cytostatic activity toward nine cancerous cell lines and several of them appeared slightly active for Capan-1, Hap1 and HCT-116 cells values of IC50 in the range 14.5-97.9 µM. Compound trans-11f was identified as adjuvant of oxacillin with significant ability to enhance the efficacy of this antibiotic toward the highly resistant S. aureus strain HEMSA 5. Docking and molecular dynamics simulations showed that enantiomer (3R,4S)-11f can be responsible for the promising activity due to the potency in displacing oxacillin at ß-lactamase, thus protecting the antibiotic from undesirable biotransformation.


Subject(s)
Adjuvants, Pharmaceutic/chemistry , Adjuvants, Pharmaceutic/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Azetidines/pharmacology , Infections/drug therapy , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Azetidines/chemistry , Bacterial Proteins/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Coronavirus 229E, Human/drug effects , Cytostatic Agents/chemistry , Cytostatic Agents/pharmacology , Humans , Influenza A Virus, H1N1 Subtype/drug effects , Molecular Dynamics Simulation , Oxacillin/chemistry , Penicillin-Binding Proteins/chemistry , Staphylococcus aureus/drug effects , Stereoisomerism , beta-Lactamases/chemistry
6.
J Clin Pharmacol ; 61(10): 1274-1285, 2021 10.
Article in English | MEDLINE | ID: covidwho-1192122

ABSTRACT

Baricitinib is a JAK1/2 inhibitor that was first approved for treating moderate to severe rheumatoid arthritis (RA) but that later showed considerable efficacy in the control of exaggerated inflammatory responses that occur in a wide range of diseases. There is a growing body of evidence, obtained from clinical trials and case reports, demonstrating clinical and paraclinical improvement in patients following administration of baricitinib including RA, systemic lupus erythematosus, psoriasis, atopic dermatitis, alopecia areata, interferon-mediated autoinflammatory diseases, graft-versus-host disease, diabetic kidney disease, and, recently, coronavirus disease-19. However, despite overall encouraging results, many adverse effects have been observed in baricitinib-treated patients, ranging from simple infections to increased risk of malignancies, particularly in long-term use. The significant efficacy of baricitinib, versus the probable adverse effects, urge further investigation before establishing it as a part of standard therapeutic protocols. Here, we have provided a review of the studies that have used baricitinib for treating various inflammatory disorders and summarized the advantages and disadvantages of its administration.


Subject(s)
Arthritis, Rheumatoid/drug therapy , Azetidines/pharmacology , COVID-19 , Inflammation/drug therapy , Purines/pharmacology , Pyrazoles/pharmacology , Sulfonamides/pharmacology , COVID-19/drug therapy , COVID-19/immunology , Humans , Janus Kinase Inhibitors/pharmacology , Risk Assessment , SARS-CoV-2 , Treatment Outcome
7.
Sci Rep ; 11(1): 2512, 2021 01 28.
Article in English | MEDLINE | ID: covidwho-1054059

ABSTRACT

Whenever some phenomenon can be represented as a graph or a network it seems pertinent to explore how much the mathematical properties of that network impact the phenomenon. In this study we explore the same philosophy in the context of immunology. Our objective was to assess the correlation of "size" (number of edges and minimum vertex cover) of the JAK/STAT network with treatment effect in rheumatoid arthritis (RA), phenotype of viral infection and effect of immunosuppressive agents on a system infected with the coronavirus. We extracted the JAK/STAT pathway from Kyoto Encyclopedia of Genes and Genomes (KEGG, hsa04630). The effects of the following drugs, and their combinations, commonly used in RA were tested: methotrexate, prednisolone, rituximab, tocilizumab, tofacitinib and baricitinib. Following viral systems were also tested for their ability to evade the JAK/STAT pathway: Measles, Influenza A, West Nile virus, Japanese B virus, Yellow Fever virus, respiratory syncytial virus, Kaposi's sarcoma virus, Hepatitis B and C virus, cytomegalovirus, Hendra and Nipah virus and Coronavirus. Good correlation of edges and minimum vertex cover with clinical efficacy were observed (for edge, rho = - 0.815, R2 = 0.676, p = 0.007, for vertex cover rho = - 0.793, R2 = 0.635, p = 0.011). In the viral systems both edges and vertex cover were associated with acuteness of viral infections. In the JAK/STAT system already infected with coronavirus, maximum reduction in size was achieved with baricitinib. To conclude, algebraic and combinatorial invariant of a network may explain its biological behaviour. At least theoretically, baricitinib may be an attractive target for treatment of coronavirus infection.


Subject(s)
Arthritis, Rheumatoid/metabolism , Janus Kinases/metabolism , STAT Transcription Factors/metabolism , Virus Diseases/drug therapy , Virus Diseases/metabolism , Antibodies, Monoclonal, Humanized/pharmacology , Arthritis, Rheumatoid/genetics , Azetidines/pharmacology , Gene Regulatory Networks , Humans , Janus Kinases/genetics , Methotrexate/pharmacology , Models, Statistical , Piperidines/pharmacology , Prednisolone/pharmacology , Purines/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Rituximab/pharmacology , STAT Transcription Factors/genetics , Signal Transduction/drug effects , Sulfonamides/pharmacology
9.
Ann Palliat Med ; 10(1): 707-720, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1030457

ABSTRACT

The whole world is battling through coronavirus disease 2019 (COVID-19) which is a fatal pandemic. In the early 2020, the World Health Organization (WHO) declared it as a global health emergency without definitive treatments and preventive approaches. In the absence of definitive therapeutic agents, this thorough review summarizes and outlines the potency and safety of all molecules and therapeutics which may have potential antiviral effects. A number of molecules and therapeutics licensed or being tested for some other conditions were found effective in different in vitro studies as well as in many small sample-sized clinical trials and independent case studies. However, in those clinical trials, there were some limitations which need to be overcome to find the most promising antiviral against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In conclusion, many of above-mentioned antivirals seems to have some therapeutic effects but none of them have been shown to have a strong evidence for their proper recommendation and approval in the treatment of COVID-19. Constantly evolving new evidences, exclusive adult data, language barrier, and type of study (observational, retrospective, small-sized clinical trials, or independent case series) resulted to the several limitations of this review. The need for multicentered, large sample-sized, randomized, placebo-controlled trials on COVID-19 patients to reach a proper conclusion on the most promising antiviral agent is warranted.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/therapy , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/pharmacology , Alanine/therapeutic use , Amides/pharmacology , Amides/therapeutic use , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , Azetidines/pharmacology , Azetidines/therapeutic use , Chloroquine/pharmacology , Chloroquine/therapeutic use , Drug Combinations , Humans , Hydroxychloroquine/pharmacology , Hydroxychloroquine/therapeutic use , Immunization, Passive , Indoles/pharmacology , Indoles/therapeutic use , Interferons/pharmacology , Interferons/therapeutic use , Ivermectin/pharmacology , Ivermectin/therapeutic use , Lopinavir/pharmacology , Lopinavir/therapeutic use , Nitro Compounds , Oseltamivir/pharmacology , Oseltamivir/therapeutic use , Purines/pharmacology , Purines/therapeutic use , Pyrazines/pharmacology , Pyrazines/therapeutic use , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Ribavirin/pharmacology , Ribavirin/therapeutic use , Ritonavir/pharmacology , Ritonavir/therapeutic use , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Thiazoles/pharmacology , Thiazoles/therapeutic use
10.
Theranostics ; 11(1): 316-329, 2021.
Article in English | MEDLINE | ID: covidwho-922935

ABSTRACT

Severe coronavirus disease 2019 (COVID-19) is characterized by systemic hyper-inflammation, acute respiratory distress syndrome, and multiple organ failure. Cytokine storm refers to a set of clinical conditions caused by excessive immune reactions and has been recognized as a leading cause of severe COVID-19. While comparisons have been made between COVID-19 cytokine storm and other kinds of cytokine storm such as hemophagocytic lymphohistiocytosis and cytokine release syndrome, the pathogenesis of cytokine storm has not been clearly elucidated yet. Recent studies have shown that impaired response of type-1 IFNs in early stage of COVID-19 infection played a major role in the development of cytokine storm, and various cytokines such as IL-6 and IL-1 were involved in severe COVID-19. Furthermore, many clinical evidences have indicated the importance of anti-inflammatory therapy in severe COVID-19. Several approaches are currently being used to treat the observed cytokine storm associated with COVID-19, and expectations are especially high for new cytokine-targeted therapies, such as tocilizumab, anakinra, and baricitinib. Although a number of studies have been conducted on anti-inflammatory treatments for severe COVID-19, no specific recommendations have been made on which drugs should be used for which patients and when. In this review, we provide an overview of cytokine storm in COVID-19 and treatments currently being used to address it. In addition, we discuss the potential therapeutic role of extracorporeal cytokine removal to treat the cytokine storm associated with COVID-19.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/complications , Cytokine Release Syndrome/immunology , Cytokines/metabolism , Immunosuppressive Agents/therapeutic use , Anti-Inflammatory Agents/pharmacology , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , Azetidines/pharmacology , Azetidines/therapeutic use , COVID-19/drug therapy , COVID-19/immunology , COVID-19/virology , Clinical Trials as Topic , Cytokine Release Syndrome/drug therapy , Cytokines/antagonists & inhibitors , Cytokines/immunology , Humans , Immunosuppressive Agents/pharmacology , Interleukin 1 Receptor Antagonist Protein/pharmacology , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Janus Kinases/antagonists & inhibitors , Janus Kinases/metabolism , Purines/pharmacology , Purines/therapeutic use , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , SARS-CoV-2/immunology , STAT Transcription Factors/antagonists & inhibitors , STAT Transcription Factors/metabolism , Severity of Illness Index , Signal Transduction/drug effects , Signal Transduction/immunology , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Treatment Outcome
11.
Mini Rev Med Chem ; 21(6): 704-723, 2021.
Article in English | MEDLINE | ID: covidwho-922755

ABSTRACT

The current pandemic of COVID-19 caused by SARS-Cov-2 has posed a severe threat to the whole world with its highly infectious, progressive nature with up to 10% mortality rates. The severity of the situation faced by the whole world and the lack of efficient therapeutics to treat this viral disease have led the WHO to depend on the drug-repurposing approach to tackle this major global health problem. This review aims at highlighting the various synthetic approaches employed for the synthesis of these FDA approved drugs that have been presently used for COVID-19 treatment. Additionally, a brief overview of several therapeutic strategies is also presented. This review will encourage the scientific community across the globe to come up with better and efficient synthetic protocols and also novel chemical entities along with this core with more potent activity.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Repositioning/methods , SARS-CoV-2/drug effects , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Azetidines/chemical synthesis , Azetidines/chemistry , Azetidines/pharmacology , Azetidines/therapeutic use , Chemistry Techniques, Synthetic/methods , Humans , Nitriles , Purines/chemical synthesis , Purines/chemistry , Purines/pharmacology , Purines/therapeutic use , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Pyrimidines , SARS-CoV-2/physiology , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Virus Internalization/drug effects
12.
Bioorg Chem ; 104: 104320, 2020 11.
Article in English | MEDLINE | ID: covidwho-848890

ABSTRACT

In the present study, we intend to synthesize a series of novel substituted phenyl azetidine-2-one sulphonyl derivatives. The entire set of derivatives 5 (a-t) were screened for in-vitro antibacterial, and antifungal activity, and among them eleven compounds were further screened for the antiviral activity to predict their efficacy against pathogenic viruses. Interestingly, compound 5d, 5e, 5f, 5h, 5i, and 5j showed similar or better antibacterial activity as compared to ampicillin (standard). Moreover, compounds 5h, 5i, 5j, and 5q showed good inhibitory activity against fungal strains whereas other derivatives had mild or diminished activity in comparison with standard drug clotrimazole. The antimicrobial study indicated that compounds having electron-withdrawing groups showed the highest activity. Interestingly, these tested compounds showed weak antiviral activity against Vaccinia virus, Human Coronavirus (229E), Reovirus-1, Herpes simplex virus, Sindbis virus, Coxsackievirus B4, Yellow Fever virus, and Influenza B virus in HEL cell, Vero cell, and MDCK cell cultures. The findings of the present study might open new avenues to target human disease-causing deadly microbes and viruses.


Subject(s)
Anti-Bacterial Agents/pharmacology , Antifungal Agents/pharmacology , Antiviral Agents/pharmacology , Azetidines/pharmacology , Sulfonamides/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Antifungal Agents/chemical synthesis , Antiviral Agents/chemical synthesis , Aspergillus fumigatus/drug effects , Aspergillus niger/drug effects , Azetidines/chemical synthesis , Candida albicans/drug effects , Cell Line, Tumor , Chlorocebus aethiops , Dogs , Escherichia coli/drug effects , Humans , Madin Darby Canine Kidney Cells , Microbial Sensitivity Tests , Molecular Structure , Pseudomonas aeruginosa/drug effects , Staphylococcus aureus/drug effects , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Vero Cells , Viruses/drug effects
13.
Expert Opin Biol Ther ; 21(2): 219-228, 2021 02.
Article in English | MEDLINE | ID: covidwho-735642

ABSTRACT

INTRODUCTION: SARS-CoV-2 is a novel coronavirus that was first isolated from a group of patients hospitalized with pneumonia in China at the end of 2019, and, in February 2020, the syndrome it caused was named coronavirus disease 2019 (COVID-19) by the World Health Organization. In the absence of specific antiviral treatments capable of neutralizing the etiological agent, one therapeutic approach is to control the cytokine storm responsible for the most severe forms of the disease. The characteristic cytokine profile of severely affected patients is increased levels of interleukin (IL)-1ß, IL-2, IL-6, IL-7, IL-8, and tumor necrosis factor alpha (TNF-α). AREAS COVERED: This article discusses the pathogenesis of COVID-19 as a rationale for using the biological and targeted synthetic drugs used in rheumatology (anti-TNF, anti-IL-1 and anti-IL-6 agents and baricitinib) to treat the disease, and provides key information concerning their potential benefits and adverse effects. EXPERT OPINION: Interleukin inhibition seems to be a promising means of treating COVID-19 patients when respiratory function declines (or even earlier) if there are laboratory data indicating the presence of a cytokine storm because the interleukins are key drivers of inflammation. However, it is important to consider the risks and benefits of biological agents carefully, and critically analyze the evidence concerning their use in COVID-19 patients.


Subject(s)
Antirheumatic Agents/therapeutic use , COVID-19/drug therapy , Cytokines/antagonists & inhibitors , Rheumatology/methods , SARS-CoV-2/drug effects , Antirheumatic Agents/pharmacology , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Azetidines/pharmacology , Azetidines/therapeutic use , COVID-19/epidemiology , COVID-19/metabolism , China/epidemiology , Clinical Trials as Topic/methods , Cytokines/metabolism , Humans , Immunosuppressive Agents/pharmacology , Immunosuppressive Agents/therapeutic use , Purines/pharmacology , Purines/therapeutic use , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , SARS-CoV-2/metabolism , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Treatment Outcome , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolism
14.
Int Immunopharmacol ; 86: 106749, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-622031

ABSTRACT

In December 2019, a novel coronavirus pneumonia (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suddenly broke out in China and rapidly spread all over the world. Recently, a cell surface protein, known as angiotensin-converting enzyme II (ACE2), has been identified to be involved in receptor-mediated endocytosis for SARS-CoV-2 entry to the cells. Many studies have reported the clinical characteristics of COVID-19: sudden deterioration of disease around 1-2 weeks after onset; much lower level of lymphocytes, especially natural killer (NK) cells in peripheral blood; extremely high pro-inflammatory cytokines and C reactive protein (CRP). About 15.7% of patients develop severe pneumonia, and cytokine storm is an important factor leading to rapid disease progression. Currently, there are no specific drugs for COVID-19 and the cytokine storm it causes. Baricitinib intracellularly inhibits the proinflammatory signal of several cytokines by suppressing Janus kinase (JAK) JAK1/JAK2. It has been demonstrated clinical benefits for the patients with rheumatoid arthritis (RA), active systemic lupus erythematosus and atopic dermatitis with good efficacy and safety records. Baricitinib is expected to interrupt the passage and intracellular assembly of SARS-CoV-2 into the target cells mediated by ACE2 receptor, and treat cytokine storm caused by COVID-19. Several clinical trials are currently investigating the drug, and one of which has been completed with encouraging results. In this paper, we will elaborate the role of cytokine storm mediated by JAK-STAT pathway in severe COVID-19, the possible mechanisms of baricitinib on reducing the viral entry into the target cells and cytokine storm, the key points of pharmaceutical care based on the latest research reports, clinical trials progress and drug instruction from the US FDA, so as to provide reference for the treatment of severe COVID-19.


Subject(s)
Azetidines/therapeutic use , Betacoronavirus/immunology , Coronavirus Infections/drug therapy , Cytokine Release Syndrome/drug therapy , Pneumonia, Viral/drug therapy , Signal Transduction/drug effects , Sulfonamides/therapeutic use , Angiotensin-Converting Enzyme 2 , Azetidines/pharmacology , Betacoronavirus/metabolism , COVID-19 , Clinical Trials as Topic , Coronavirus Infections/complications , Coronavirus Infections/diagnosis , Coronavirus Infections/immunology , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Cytokines/immunology , Cytokines/metabolism , Humans , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 1/metabolism , Janus Kinase 2/antagonists & inhibitors , Janus Kinase 2/metabolism , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/complications , Pneumonia, Viral/diagnosis , Pneumonia, Viral/immunology , Purines , Pyrazoles , SARS-CoV-2 , Severity of Illness Index , Signal Transduction/immunology , Sulfonamides/pharmacology , Treatment Outcome , Virus Assembly/drug effects , Virus Internalization/drug effects
15.
Pharmacotherapy ; 40(8): 843-856, 2020 08.
Article in English | MEDLINE | ID: covidwho-602791

ABSTRACT

A hyperinflammatory response to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, reminiscent of cytokine release syndrome, has been implicated in the pathophysiology of acute respiratory distress syndrome and organ damage in patients with coronavirus disease 2019 (COVID-19). Agents that inhibit components of the pro-inflammatory cascade have garnered interest as potential treatment options with hopes that dampening the proinflammatory process may improve clinical outcomes. Baricitinib is a reversible Janus-associated kinase (JAK)-inhibitor that interrupts the signaling of multiple cytokines implicated in COVID-19 immunopathology. It may also have antiviral effects by targeting host factors that viruses rely for cell entry and by suppressing type I interferon driven angiotensin-converting-enzyme-2 upregulation. However, baricitinib's immunosuppressive effects may be detrimental during acute viral infections by delaying viral clearance and increasing vulnerability to secondary opportunistic infections. The lack of reliable biomarkers to monitor patients' immune status as illness evolves complicates deployment of immunosuppressive drugs like baricitinib. Furthermore, baricitinib carries the risk of increased thromboembolic events, which is concerning given the proclivity towards a hypercoagulable state in patients with COVID-19. In this article, we review available data on baricitinib with an emphasis on immunosuppressive and antiviral pharmacology, pharmacokinetics, safety, and current progress in COVID-19 clinical trials.


Subject(s)
Azetidines/pharmacology , Azetidines/therapeutic use , Coronavirus Infections/complications , Inflammation/drug therapy , Inflammation/etiology , Janus Kinases/antagonists & inhibitors , Pneumonia, Viral/complications , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Angiotensin-Converting Enzyme 2 , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Area Under Curve , Azetidines/administration & dosage , Azetidines/adverse effects , Betacoronavirus , COVID-19 , Clinical Trials as Topic , Cytokines/metabolism , Drug Interactions , Humans , Interferon Type I/biosynthesis , Metabolic Clearance Rate , Pandemics , Peptidyl-Dipeptidase A/biosynthesis , Purines , Pyrazoles , SARS-CoV-2 , Signal Transduction/drug effects , Sulfonamides/administration & dosage , Sulfonamides/adverse effects
16.
EMBO Mol Med ; 12(8): e12697, 2020 08 07.
Article in English | MEDLINE | ID: covidwho-434202

ABSTRACT

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 , Purines , Pyrazoles , SARS-CoV-2 , Spheroids, Cellular/drug effects , Spheroids, Cellular/virology , Sulfonamides/pharmacokinetics , Sulfonamides/therapeutic use
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