Sunitinib reduces the infection of SARS-CoV, MERS-CoV and SARS-CoV-2 partially by inhibiting AP2M1 phosphorylation.
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ABSTRACT:
SUBMITTER: Wang PG
PROVIDER: S-EPMC7550610 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
Publications
Sunitinib reduces the infection of SARS-CoV, MERS-CoV and SARS-CoV-2 partially by inhibiting AP2M1 phosphorylation.
Wang Pei-Gang PG Tang Dong-Jiang DJ Hua Zhan Z Wang Zai Z An Jing J
Cell discovery 20201013
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Project description:Abstract: SARS-CoV-2 acute respiratory distress syndrome (ARDS) induces uncontrolled lung inflammation and coagulopathy with high mortality. Anti-viral drugs and monoclonal antibodies reduce early COVID-19 severity, but treatments for late-stage immuno-thrombotic syndromes and long COVID are limited. Serine protease inhibitors (SERPINS) regulate activated proteases. The myxoma virus-derived Serp-1 protein is a secreted immunomodulatory serpin that targets activated thrombotic, thrombolytic and complement proteases as a self-defense strategy to combat clearance. Serp-1 is effective in multiple animal models of inflammatory lung disease and vasculitis. Here, we describe systemic treatment with purified PEGylated Serp-1 as a therapy for immune-coagulopathic complications during ARDS. Treatment with PEGSerp-1 in two mouse-adapted SARS-CoV-2 models in C57Bl/6 and BALB/c mice reduced lung and heart inflammation, with improved outcomes. PEGSerp-1 significantly reduced M1 macrophages in the lung and heart by modifying urokinase-type plasminogen activator receptor (uPAR), thrombotic proteases and complement membrane attack complex (MAC). Sequential changes in gene expression for uPAR and serpins (complement and plasminogen inhibitors) were observed. PEGSerp-1 is a highly effective immune-modulator with therapeutic potential for severe viral ARDS, immune-coagulopathic responses and Long COVID.
| S-SCDT-10_15252-EMMM_202317376 | biostudies-other
Project description:Coronaviruses (CoVs) are important human pathogens for which no specific treatment is available. Here, we provide evidence that pharmacological reprogramming of ER stress pathways can be exploited to suppress CoV replication. We found that the ER stress inducer thapsigargin efficiently inhibits coronavirus (HCoV-229E, MERS-CoV, SARS-CoV-2) replication in different cell types, (partially) restores the virus-induced translational shut-down, and counteracts the CoV-mediated downregulation of IRE1α and the ER chaperone BiP. Proteome-wide data sets revealed specific pathways, protein networks and components that likely mediate the thapsigargin-induced antiviral state, including HERPUD1, an essential factor of ER quality control, and ER-associated protein degradation complexes. The data show that thapsigargin hits a central mechanism required for CoV replication, suggesting that thapsigargin (or derivatives thereof) may be developed into broad-spectrum anti-CoV drugs.
2021-06-24 | PXD021222 | Pride
Project description:IntroductionSince its outbreak in December 2019, SARS-CoV-2 has spread rapidly across the world, posing significant threats and challenges to global public health. SARS-CoV-2, together with SARS-CoV and MERS-CoV, is a highly pathogenic coronavirus that contributes to fatal pneumonia. Understanding the similarities and differences at the transcriptome level between SARS-CoV-2, SARS-CoV, as well as MERS-CoV is critical for developing effective strategies against these viruses.MethodsIn this article, we comparatively analyzed publicly available transcriptome data of human cell lines infected with highly pathogenic SARS-CoV-2, SARS-CoV, MERS-CoV, and lowly pathogenic HCoV-229E. The host gene expression profiles during human coronavirus (HCoV) infections were generated, and the pathways and biological functions involved in immune responses, antiviral efficacy, and organ damage were intensively elucidated.ResultsOur results indicated that SARS-CoV-2 induced a stronger immune response versus the other two highly pathogenic HCoVs. Specifically, SARS-CoV-2 induced robust type I and type III IFN responses, marked by higher upregulation of type I and type III IFNs, as well as numerous interferon-stimulated genes (ISGs). Further Ingenuity Pathway Analysis (IPA) revealed the important role of ISGs for impeding SARS-CoV-2 infection, and the interferon/ISGs could be potential targets for therapeutic interventions. Moreover, our results uncovered that SARS-CoV-2 infection was linked to an enhanced risk of multi-organ toxicity in contrast to the other two highly pathogenic HCoVs.DiscussionThese findings provided valuable insights into the pathogenic mechanism of SARS-CoV-2, which showed a similar pathological feature but a lower fatality rate compared to SARS-CoV and MERS-CoV.
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Project description:Early in the COVID-19 pandemic, data suggested that males had a higher risk of developing severe disease and that androgen deprivation therapy might be associated with protection. Combined with the fact that TMPRSS2, a host entry factor for the SARS-CoV-2 virus, was a well-known androgen-regulated gene, this led to an upsurge of research investigating androgen receptor (AR)-targeting drugs. Proxalutamide, a newer AR antagonist, was shown in initial clinical studies to benefit COVID-19 patients; however, further validation is needed as one study was retracted. Due to continued interest in proxalutamide, which is in several phase 3 trials, we examined its ability to impact SARS-CoV-2 infection and associated downstream inflammatory responses. Proxalutamide exerted similar effects as enzalutamide, an AR antagonist commonly prescribed for advanced prostate cancer treatment, in decreasing AR signaling and expression of TMPRSS2 and ACE2, the SARS-CoV-2 receptor. However, proxalutamide led to degradation of AR protein, an effect that was not observed with enzalutamide. Proxalutamide inhibited SARS-CoV-2 infection with an IC50 value of 97 nM, compared to 281 nM for enzalutamide. Importantly, proxalutamide inhibited infection by multiple SARS-CoV-2 variants and synergized with remdesivir. Proxalutamide also protected against cell death in response to TNF and IFN, and overall survival of mice was increased with proxalutamide treatment prior to cytokine exposure. Mechanistically, we found that proxalutamide increased levels of NRF2, an essential transcription factor that mediates antioxidant responses, and could decrease lung inflammation. These data provide compelling evidence that proxalutamide can prevent SARS-CoV-2 infection and cytokine-induced lung damage, suggesting that promising clinical data may emerge from ongoing phase 3 trials.
2023-06-19 | GSE234805 | GEO
Project description:The highly pathogenic MERS-CoV, SARS-CoV and SARS-CoV-2 cause acute respiratory syndrome and are often fatal. These new viruses pose major problems to global health in general and primarily to infection control and public health services. Accurate and selective assessment of MERS-CoV, SARS-CoV and SARS-CoV-2 would assist in the effective diagnosis of infected individual, offer clinical guidance and aid in assessing clinical outcomes. In this mini-review, we review the literature on various aspects, including the history and diversity of SARS-CoV-2, SARS-CoV and MERS-CoV, their detection methods in effective clinical diagnosis, clinical assessment of COVID-19, safety guidelines recommended by World Health Organization and legal regulations. This review article also deals with existing challenges and difficulties in the clinical diagnosis of SARS-CoV-2. Developing alternative diagnostic platforms by spotting the shortcomings of the existing point-of-care diagnostic devices would be useful in preventing future outbreaks.
| S-EPMC7833337 | biostudies-literature
Project description:BackgroundThe ongoing global COVID-19 pandemic is caused by SARS-CoV-2, a novel coronavirus first discovered at the end of 2019. It has led to more than 50 million confirmed cases and more than 1 million deaths across 219 countries as of 11 November 2020, according to WHO statistics. SARS-CoV-2, SARS-CoV, and MERS-CoV are similar. They are highly pathogenic and threaten public health, impair the economy, and inflict long-term impacts on society. No drug or vaccine has been approved as a treatment for these viruses. Efforts to develop antiviral measures have been hampered by the insufficient understanding of how the human body responds to viral infections at the cellular and molecular levels.ResultsIn this study, journal articles and transcriptomic and proteomic data surveying coronavirus infections were collected. Response genes and proteins were then identified by differential analyses comparing gene/protein levels between infected and control samples. Finally, the H2V database was created to contain the human genes and proteins that respond to SARS-CoV-2, SARS-CoV, and MERS-CoV infection.ConclusionsH2V provides molecular information about the human response to infection. It can be a powerful tool to discover cellular pathways and processes relevant for viral pathogenesis to identify potential drug targets. It is expected to accelerate the process of antiviral agent development and to inform preparations for potential future coronavirus-related emergencies. The database is available at: http://www.zhounan.org/h2v .
| S-EPMC7789886 | biostudies-literature
Project description:Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has posed a considerable threat to public health and global economies. SARS-CoV-2 has largely affected a vast world population and was declared a COVID-19 pandemic outbreak, with a substantial surge of SARS-CoV-2 infection affecting all aspects of the virus' natural course of infection and immunity. The cross-reactivity between the different coronaviruses is still a knowledge gap in the understanding of the SARS-CoV-2 virus. This study aimed to investigate the impact of MERS-CoV and SARS-CoV-2 viral infections on immunoglobulin-IgG cross-reactivity. Our retrospective cohort study hypothesized the possible reactivation of immunity in individuals with a history of infection to Middle East Respiratory Syndrome coronavirus (MERS-CoV) when infected with SARS-CoV-2. The total number of participants included was 34; among them, 22 (64.7%) were males, and 12 (35.29%) were females. The mean age of the participants was 40.3 ± 12.9 years. This study compared immunoglobulin (IgG) levels against SARS-CoV-2 and MERS-CoV across various groups with various histories of infection. The results showed that a reactive borderline IgG against both MERS-CoV and SARS-CoV-2 in participants with past infection to both viruses was 40% compared with 37.5% among those with past infection with MERS-CoV alone. Our study results establish that individuals infected with both SARS-CoV-2 and MERS-CoV showed higher MERS-CoV IgG levels compared with those of individuals infected previously with MERS-CoV alone and compared with those of individuals in the control. The results further highlight cross-adaptive immunity between MERS-CoV and SARS-CoV. Our study concludes that individuals with previous infections with both MERS-CoV and SARS-CoV-2 showed significantly higher MERS-CoV IgG levels compared with those of individuals infected only with MERS-CoV and compared with those of individuals in the control, suggesting cross-adaptive immunity between MERS-CoV and SARS-CoV.
| S-EPMC10054476 | biostudies-literature
Project description:Since the beginning of the COVID-19 pandemic, large in silico screening studies and numerous in vitro studies have assessed the antiviral activity of various drugs on SARS-CoV-2. In the context of health emergency, drug repurposing represents the most relevant strategy because of the reduced time for approval by international medicines agencies, the low cost of development and the well-known toxicity profile of such drugs. Herein, we aim to review drugs with in vitro antiviral activity against SARS-CoV-2, combined with molecular docking data and results from preliminary clinical studies. Finally, when considering all these previous findings, as well as the possibility of oral administration, 11 molecules consisting of nelfinavir, favipiravir, azithromycin, clofoctol, clofazimine, ivermectin, nitazoxanide, amodiaquine, heparin, chloroquine and hydroxychloroquine, show an interesting antiviral activity that could be exploited as possible drug candidates for COVID-19 treatment.
| S-EPMC8579950 | biostudies-literature
Project description:ImportanceIn the ongoing COVID-19 pandemic, there remain unanswered questions regarding the nature and importance of the humoral immune response against other coronaviruses. Although coinfection of the Middle East respiratory syndrome coronavirus (MERS-CoV) with the SARS-CoV-2 has not been documented yet, several patients previously infected with MERS-CoV received the COVID-19 vaccine; data describing how preexisting MERS-CoV immunity may shape the response to SARS-CoV-2 following infection or vaccination are lacking.ObjectiveTo characterize the cross-reactive and protective humoral responses in patients exposed to both MERS-CoV infection and SARS-CoV-2 vaccination.Design, setting, and participantsThis cohort study involved a total of 18 sera samples collected from 14 patients with MERS-CoV infection before (n = 12) and after (n = 6) vaccination with 2 doses of COVID-19 mRNA vaccine (BNT162b2 or mRNA-1273). Of those patients, 4 had prevaccination and postvaccination samples. Antibody responses to SARS-CoV-2 and MERS-CoV were assessed as well as cross-reactive responses to other human coronaviruses.Main outcomes and measuresThe main outcomes measured were binding antibody responses, neutralizing antibodies, and antibody-dependent cellular cytotoxicity (ADCC) activity. Binding antibodies targeting SARS-CoV-2 main antigens (spike [S], nucleocapsid, and receptor-binding domain) were detected using automated immunoassays. Cross-reactive antibodies with the S1 protein of SARS-CoV, MERS-CoV, and common human coronaviruses were analyzed using a bead-based assay. Neutralizing antibodies (NAbs) against MERS-CoV and SARS-CoV-2 as well as ADCC activity against SARS-CoV-2 were assessed.ResultsA total of 18 samples were collected from 14 male patients with MERS-CoV infection (mean [SD] age, 43.8 [14.6] years). Median (IQR) duration between primary COVID-19 vaccination and sample collection was 146 (47-189) days. Prevaccination samples had high levels of anti-MERS S1 immunoglobin M (IgM) and IgG (reactivity index ranging from 0.80 to 54.7 for IgM and from 0.85 to 176.3 for IgG). Cross-reactive antibodies with SARS-CoV and SARS-CoV-2 were also detected in these samples. However, cross-reactivity against other coronaviruses was not detected by the microarray assay. Postvaccination samples showed significantly higher levels of total antibodies, IgG, and IgA targeting SARS-CoV-2 S protein compared with prevaccination samples (eg, mean total antibodies: 8955.0 AU/mL; 95% CI, -5025.0 to 22936.0 arbitrary units/mL; P = .002). In addition, significantly higher anti-SARS S1 IgG levels were detected following vaccination (mean reactivity index, 55.4; 95% CI, -9.1 to 120.0; P = .001), suggesting potential cross-reactivity with these coronaviruses. Also, anti-S NAbs were significantly boosted against SARS-CoV-2 (50.5% neutralization; 95% CI, 17.6% to 83.2% neutralization; P < .001) after vaccination. Furthermore, there was no significant increase in antibody-dependent cellular cytotoxicity against SARS-CoV-2 S protein postvaccination.Conclusions and relevanceThis cohort study found a significant boost in cross-reactive NAbs in some patients exposed to MERS-CoV and SARS-CoV-2 antigens. These findings suggest that isolation of broadly reactive antibodies from these patients may help guide the development of a pancoronavirus vaccine by targeting cross-reactive epitopes between distinct strains of human coronaviruses.
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Project description: Not available
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