RESUMEN
The nonstructural protein 1 (nsp1) of severe acute respiratory syndrome coronavirus and severe acute respiratory syndrome coronavirus 2 is a critical viral protein that suppresses host gene expression by blocking the assembly of the ribosome on host mRNAs. To understand the mechanism of inhibition of host gene expression, we sought to identify cellular proteins that interact with nsp1. Using proximity-dependent biotinylation followed by proteomic analyses of biotinylated proteins, here we captured multiple dynamic interactions of nsp1 with host cell proteins. In addition to ribosomal proteins, we identified several pre-mRNA processing proteins that interact with nsp1, including splicing factors and transcription termination proteins, as well as exosome, and stress granule (SG)-associated proteins. We found that the interactions with transcription termination factors are primarily governed by the C-terminal region of nsp1 and are disrupted by the mutation of amino acids K164 and H165 that are essential for its host shutoff function. We further show that nsp1 interacts with Ras GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) and colocalizes with G3BP1 in SGs under sodium arsenite-induced stress. Finally, we observe that the presence of nsp1 disrupts the maturation of SGs over a long period. Isolation of SG core at different times shows a gradual loss of G3BP1 in the presence of nsp1.
Asunto(s)
COVID-19/metabolismo , ARN Polimerasa Dependiente del ARN/metabolismo , SARS-CoV-2/metabolismo , Síndrome Respiratorio Agudo Grave/metabolismo , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/metabolismo , Proteínas no Estructurales Virales/metabolismo , Biotinilación , COVID-19/virología , Células HEK293 , Interacciones Huésped-Patógeno , Humanos , Proteómica , Proteínas Ribosómicas/metabolismo , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/fisiología , SARS-CoV-2/fisiología , Síndrome Respiratorio Agudo Grave/virología , Gránulos de Estrés/metabolismoRESUMEN
COVID 19 disease has become a global catastrophe over the past year that has claimed the lives of over two million people around the world. Despite the introduction of vaccines against the disease, there is still a long way to completely eradicate it. There are concerns about the complications following infection with SARS-CoV-2. This research aimed to evaluate the possible correlation between infection with SARS-CoV viruses and cancer in an in-silico study model. To do this, the relevent dataset was selected from GEO database. Identification of differentially expressed genes among defined groups including SARS-CoV, SARS-dORF6, SARS-BatSRBD, and H1N1 were screened where the |Log FC| ≥ 1and p < 0.05 were considered statistically significant. Later, the pathway enrichment analysis and gene ontology (GO) were used by Enrichr and Shiny GO databases. Evaluation with STRING online was applied to predict the functional interactions of proteins, followed by Cytoscape analysis to identify the master genes. Finally, analysis with GEPIA2 server was carried out to reveal the possible correlation between candidate genes and cancer development. The results showed that the main molecular function of up- and down-regulated genes was "double-stranded RNA binding" and actin-binding, respectively. STRING and Cytoscape analysis presented four genes, PTEN, CREB1, CASP3, and SMAD3 as the key genes involved in cancer development. According to TCGA database results, these four genes were up-regulated notably in pancreatic adenocarcinoma. Our findings suggest that pancreatic adenocarcinoma is the most probably malignancy happening after infection with SARS-CoV family.
Asunto(s)
Adenocarcinoma/etiología , COVID-19/complicaciones , Carcinogénesis/genética , Subtipo H1N1 del Virus de la Influenza A , Gripe Humana/complicaciones , Neoplasias Pancreáticas/etiología , SARS-CoV-2 , Síndrome Respiratorio Agudo Grave/complicaciones , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo , COVID-19/genética , COVID-19/metabolismo , COVID-19/virología , Caspasa 3/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Regulación de la Expresión Génica , Ontología de Genes , Humanos , Gripe Humana/genética , Gripe Humana/metabolismo , Gripe Humana/virología , Fosfohidrolasa PTEN/genética , Mapas de Interacción de Proteínas , Riesgo , Síndrome Respiratorio Agudo Grave/genética , Síndrome Respiratorio Agudo Grave/metabolismo , Síndrome Respiratorio Agudo Grave/virología , Transducción de Señal/genética , Proteína smad3/genética , Regulación hacia Arriba/genéticaRESUMEN
The SARS-CoV-2 pandemic has caused a surge in research exploring all aspects of the virus and its effects on human health. The overwhelming publication rate means that researchers are unable to keep abreast of the literature. To ameliorate this, we present the CoronaCentral resource that uses machine learning to process the research literature on SARS-CoV-2 together with SARS-CoV and MERS-CoV. We categorize the literature into useful topics and article types and enable analysis of the contents, pace, and emphasis of research during the crisis with integration of Altmetric data. These topics include therapeutics, disease forecasting, as well as growing areas such as "long COVID" and studies of inequality. This resource, available at https://coronacentral.ai, is updated daily.
Asunto(s)
COVID-19 , Aprendizaje Automático , Coronavirus del Síndrome Respiratorio de Oriente Medio/metabolismo , Pandemias , SARS-CoV-2/metabolismo , Síndrome Respiratorio Agudo Grave , Animales , COVID-19/epidemiología , COVID-19/metabolismo , COVID-19/terapia , COVID-19/transmisión , Humanos , Coronavirus del Síndrome Respiratorio de Oriente Medio/patogenicidad , SARS-CoV-2/patogenicidad , Síndrome Respiratorio Agudo Grave/epidemiología , Síndrome Respiratorio Agudo Grave/metabolismo , Síndrome Respiratorio Agudo Grave/terapia , Síndrome Respiratorio Agudo Grave/transmisiónRESUMEN
The emergence and global spread of SARS-CoV-2 has resulted in the urgent need for an in-depth understanding of molecular functions of viral proteins and their interactions with the host proteome. Several individual omics studies have extended our knowledge of COVID-19 pathophysiology1-10. Integration of such datasets to obtain a holistic view of virus-host interactions and to define the pathogenic properties of SARS-CoV-2 is limited by the heterogeneity of the experimental systems. Here we report a concurrent multi-omics study of SARS-CoV-2 and SARS-CoV. Using state-of-the-art proteomics, we profiled the interactomes of both viruses, as well as their influence on the transcriptome, proteome, ubiquitinome and phosphoproteome of a lung-derived human cell line. Projecting these data onto the global network of cellular interactions revealed crosstalk between the perturbations taking place upon infection with SARS-CoV-2 and SARS-CoV at different levels and enabled identification of distinct and common molecular mechanisms of these closely related coronaviruses. The TGF-ß pathway, known for its involvement in tissue fibrosis, was specifically dysregulated by SARS-CoV-2 ORF8 and autophagy was specifically dysregulated by SARS-CoV-2 ORF3. The extensive dataset (available at https://covinet.innatelab.org ) highlights many hotspots that could be targeted by existing drugs and may be used to guide rational design of virus- and host-directed therapies, which we exemplify by identifying inhibitors of kinases and matrix metalloproteases with potent antiviral effects against SARS-CoV-2.
Asunto(s)
COVID-19/metabolismo , Interacciones Huésped-Patógeno , Proteoma/metabolismo , Proteómica , SARS-CoV-2/patogenicidad , Síndrome Respiratorio Agudo Grave/metabolismo , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/patogenicidad , Animales , Antivirales/farmacología , Autofagia/efectos de los fármacos , COVID-19/inmunología , COVID-19/virología , Línea Celular , Conjuntos de Datos como Asunto , Evaluación Preclínica de Medicamentos , Interacciones Huésped-Patógeno/inmunología , Humanos , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Fosforilación , Mapas de Interacción de Proteínas , Inhibidores de Proteínas Quinasas/farmacología , Procesamiento Proteico-Postraduccional , Proteoma/química , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/inmunología , SARS-CoV-2/inmunología , Síndrome Respiratorio Agudo Grave/inmunología , Síndrome Respiratorio Agudo Grave/virología , Factor de Crecimiento Transformador beta/metabolismo , Ubiquitinación , Proteínas Virales/química , Proteínas Virales/metabolismo , Proteínas Viroporinas/metabolismoRESUMEN
Recently, the novel coronavirus (SARS-CoV-2), which has spread from China to the world, was declared a global public health emergency, which causes lethal respiratory infections. Acetylation of several proteins plays essential roles in various biological processes, such as viral infections. We reported that the nucleoproteins of influenza virus and Zaire Ebolavirus were acetylated, suggesting that these modifications contributed to the molecular events involved in viral replication. Similar to influenza virus and Ebolavirus, the coronavirus also contains single-stranded RNA, as its viral genome interacts with the nucleocapsid (N) proteins. In this study, we report that SARS-CoV and SARS-CoV-2 N proteins are strongly acetylated by human histone acetyltransferases, P300/CBP-associated factor (PCAF), and general control nonderepressible 5 (GCN5), but not by CREB-binding protein (CBP) in vitro. Liquid chromatography-mass spectrometry analyses identified 2 and 12 acetyl-lysine residues from SARS-CoV and SARS-CoV-2 N proteins, respectively. Particularly in the SARS-CoV-2 N proteins, the acetyl-lysine residues were localized in or close to several functional sites, such as the RNA interaction domains and the M-protein interacting site. These results suggest that acetylation of SARS-CoV-2 N proteins plays crucial roles in their functions.
Asunto(s)
COVID-19/metabolismo , Proteínas de la Nucleocápside de Coronavirus/metabolismo , Histona Acetiltransferasas/metabolismo , SARS-CoV-2/metabolismo , Síndrome Respiratorio Agudo Grave/metabolismo , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/metabolismo , Factores de Transcripción p300-CBP/metabolismo , Acetilación , Proteína de Unión a CREB/metabolismo , Proteínas de la Nucleocápside de Coronavirus/química , Humanos , Modelos Moleculares , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/química , SARS-CoV-2/químicaRESUMEN
The pathogenesis of SARS-CoV-2 remains to be completely understood, and detailed SARS-CoV-2 cellular cytopathic effects requires definition. We performed a comparative ultrastructural study of SARS-CoV-1 and SARS-CoV-2 infection in Vero E6 cells and in lungs from deceased COVID-19 patients. SARS-CoV-2 induces rapid death associated with profound ultrastructural changes in Vero cells. Type II pneumocytes in lung tissue showed prominent altered features with numerous vacuoles and swollen mitochondria with presence of abundant lipid droplets. The accumulation of lipids was the most striking finding we observed in SARS-CoV-2 infected cells, both in vitro and in the lungs of patients, suggesting that lipids can be involved in SARS-CoV-2 pathogenesis. Considering that in most cases, COVID-19 patients show alteration of blood cholesterol and lipoprotein homeostasis, our findings highlight a peculiar important topic that can suggest new approaches for pharmacological treatment to contrast the pathogenicity of SARS-CoV-2.
Asunto(s)
COVID-19 , Gotas Lipídicas , Metabolismo de los Lípidos , Pulmón , SARS-CoV-2/metabolismo , Animales , COVID-19/metabolismo , COVID-19/patología , Chlorocebus aethiops , Efecto Citopatogénico Viral , Humanos , Gotas Lipídicas/ultraestructura , Gotas Lipídicas/virología , Pulmón/metabolismo , Pulmón/ultraestructura , Pulmón/virología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/metabolismo , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/ultraestructura , SARS-CoV-2/ultraestructura , Síndrome Respiratorio Agudo Grave/metabolismo , Síndrome Respiratorio Agudo Grave/patología , Células VeroRESUMEN
Coronaviruses (CoVs) are positive-sense RNA enveloped viruses, members of the family Coronaviridae, that cause infections in a broad range of mammals including humans. Several CoV species lead to mild upper respiratory infections typically associated with common colds. However, three human CoV (HCoV) species: Severe Acute Respiratory Syndrome (SARS)-CoV-1, Middle East Respiratory Syndrome (MERS)-CoV, and SARS-CoV-2, are responsible for severe respiratory diseases at the origin of two recent epidemics (SARS and MERS), and of the current COronaVIrus Disease 19 (COVID-19), respectively. The easily transmissible SARS-CoV-2, emerging at the end of 2019 in China, spread rapidly worldwide, leading the World Health Organization (WHO) to declare COVID-19 a pandemic. While the world waits for mass vaccination, there is an urgent need for effective drugs as short-term weapons to combat the SARS-CoV-2 infection. In this context, the drug repurposing approach is a strategy able to guarantee positive results rapidly. In this regard, it is well known that several nucleoside-mimicking analogs and nucleoside precursors may inhibit the growth of viruses providing effective therapies for several viral diseases, including HCoV infections. Therefore, this review will focus on synthetic nucleosides and nucleoside precursors active against different HCoV species, paying great attention to SARS-CoV-2. This work covers progress made in anti-CoV therapy with nucleoside derivatives and provides insight into their main mechanisms of action.
Asunto(s)
Antivirales , Tratamiento Farmacológico de COVID-19 , Reposicionamiento de Medicamentos , Nucleósidos , SARS-CoV-2/metabolismo , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/metabolismo , Animales , Antivirales/química , Antivirales/uso terapéutico , COVID-19/epidemiología , COVID-19/metabolismo , Humanos , Nucleósidos/química , Nucleósidos/uso terapéutico , Síndrome Respiratorio Agudo Grave/epidemiología , Síndrome Respiratorio Agudo Grave/metabolismoRESUMEN
The novel coronavirus disease, COVID-19, has grown into a global pandemic and a major public health threat since its breakout in December 2019. To date, no specific therapeutic drug or vaccine for treating COVID-19 and SARS has been FDA approved. Previous studies suggest that berberine, an isoquinoline alkaloid, has shown various biological activities that may help against COVID-19 and SARS, including antiviral, anti-allergy and inflammation, hepatoprotection against drug- and infection-induced liver injury, as well as reducing oxidative stress. In particular, berberine has a wide range of antiviral activities such as anti-influenza, anti-hepatitis C, anti-cytomegalovirus, and anti-alphavirus. As an ingredient recommended in guidelines issued by the China National Health Commission for COVID-19 to be combined with other therapy, berberine is a promising orally administered therapeutic candidate against SARS-CoV and SARS-CoV-2. The current study comprehensively evaluates the potential therapeutic mechanisms of berberine in preventing and treating COVID-19 and SARS using computational modeling, including target mining, gene ontology enrichment, pathway analyses, protein-protein interaction analysis, and in silico molecular docking. An orally available immunotherapeutic-berberine nanomedicine, named NIT-X, has been developed by our group and has shown significantly increased oral bioavailability of berberine, increased IFN-γ production by CD8+ T cells, and inhibition of mast cell histamine release in vivo, suggesting a protective immune response. We further validated the inhibition of replication of SARS-CoV-2 in lung epithelial cells line in vitro (Calu3 cells) by berberine. Moreover, the expression of targets including ACE2, TMPRSS2, IL-1α, IL-8, IL-6, and CCL-2 in SARS-CoV-2 infected Calu3 cells were significantly suppressed by NIT-X. By supporting protective immunity while inhibiting pro-inflammatory cytokines; inhibiting viral infection and replication; inducing apoptosis; and protecting against tissue damage, berberine is a promising candidate in preventing and treating COVID-19 and SARS. Given the high oral bioavailability and safety of berberine nanomedicine, the current study may lead to the development of berberine as an orally, active therapeutic against COVID-19 and SARS.
Asunto(s)
Antivirales/farmacología , Berberina/farmacología , Tratamiento Farmacológico de COVID-19 , COVID-19 , Regulación de la Expresión Génica/efectos de los fármacos , Modelos Biológicos , SARS-CoV-2/metabolismo , Síndrome Respiratorio Agudo Grave , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/metabolismo , Administración Oral , COVID-19/metabolismo , Línea Celular , Simulación por Computador , Humanos , Pandemias , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico , Síndrome Respiratorio Agudo Grave/metabolismoRESUMEN
Although vaccines are available for many infectious diseases, there are still unresolved infectious diseases that threaten global public health. In particular, the rapid spread of unpredictable, highly contagious viruses has recorded numerous infection cases and deaths, and has changed our lives socially or economically through social distancing and wearing masks. The pandemics of unpredictable, highly contagious viruses increase the ever-high social need for rapid vaccine development. Nanotechnologies may hold promise and expedite the development of vaccines against newly emerging infectious viruses. As potential nanoplatforms for delivering antigens to immune cells, delivery systems based on lipids, polymers, proteins, and inorganic nanomaterials have been studied. These nanoplatforms have been tested as a means to deliver vaccines not as a whole, but in the form of protein subunits or as DNA or mRNA sequences encoding the antigen proteins of viruses. This review covers the current status of nanomaterial-based delivery systems for viral antigens, with highlights on nanovaccines against recently emerging infectious viruses, such as severe acute respiratory syndrome coronavirus-2, Middle East respiratory syndrome coronavirus, and Zika virus.
Asunto(s)
Infecciones por Coronavirus/prevención & control , Sistemas de Liberación de Medicamentos/métodos , Nanotecnología/métodos , Vacunas Virales/administración & dosificación , Infección por el Virus Zika/prevención & control , Animales , COVID-19/inmunología , COVID-19/metabolismo , COVID-19/prevención & control , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/metabolismo , Sistemas de Liberación de Medicamentos/tendencias , Humanos , Nanotecnología/tendencias , Síndrome Respiratorio Agudo Grave/inmunología , Síndrome Respiratorio Agudo Grave/metabolismo , Síndrome Respiratorio Agudo Grave/prevención & control , Vacunas Virales/inmunología , Vacunas Virales/metabolismo , Virosis/inmunología , Virosis/metabolismo , Virosis/prevención & control , Infección por el Virus Zika/inmunología , Infección por el Virus Zika/metabolismoRESUMEN
Lithium salts have been in the therapeutic toolbox for better or worse since the 19th century, with purported benefit in gout, hangover, insomnia, and early suggestions that lithium improved psychiatric disorders. However, the remarkable effects of lithium reported by John Cade and subsequently by Mogens Schou revolutionized the treatment of bipolar disorder. The known molecular targets of lithium are surprisingly few and include the signaling kinase glycogen synthase kinase-3 (GSK-3), a group of structurally related phosphomonoesterases that includes inositol monophosphatases, and phosphoglucomutase. Here we present a brief history of the therapeutic uses of lithium and then focus on GSK-3 as a therapeutic target in diverse diseases, including bipolar disorder, cancer, and coronavirus infections.
Asunto(s)
Antimaníacos/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Compuestos de Litio/uso terapéutico , Neoplasias/tratamiento farmacológico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico , Animales , Antimaníacos/farmacología , Trastorno Bipolar/metabolismo , Coronavirus/efectos de los fármacos , Glucógeno Sintasa Quinasa 3/metabolismo , Humanos , Compuestos de Litio/farmacología , Neoplasias/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Síndrome Respiratorio Agudo Grave/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infects cells through interaction of its spike protein (SARS2-S) with angiotensin-converting enzyme 2 (ACE2) and activation by proteases, in particular transmembrane protease serine 2 (TMPRSS2). Viruses can also spread through fusion of infected with uninfected cells. We compared the requirements of ACE2 expression, proteolytic activation, and sensitivity to inhibitors for SARS2-S-mediated and SARS-CoV-S (SARS1-S)-mediated cell-cell fusion. SARS2-S-driven fusion was moderately increased by TMPRSS2 and strongly by ACE2, while SARS1-S-driven fusion was strongly increased by TMPRSS2 and less so by ACE2 expression. In contrast to that of SARS1-S, SARS2-S-mediated cell-cell fusion was efficiently activated by batimastat-sensitive metalloproteases. Mutation of the S1/S2 proteolytic cleavage site reduced effector cell-target cell fusion when ACE2 or TMPRSS2 was limiting and rendered SARS2-S-driven cell-cell fusion more dependent on TMPRSS2. When both ACE2 and TMPRSS2 were abundant, initial target cell-effector cell fusion was unaltered compared to that of wild-type (wt) SARS2-S, but syncytia remained smaller. Mutation of the S2 cleavage (S2') site specifically abrogated activation by TMPRSS2 for both cell-cell fusion and SARS2-S-driven pseudoparticle entry but still allowed for activation by metalloproteases for cell-cell fusion and by cathepsins for particle entry. Finally, we found that the TMPRSS2 inhibitor bromhexine, unlike the inhibitor camostat, was unable to reduce TMPRSS2-activated cell-cell fusion by SARS1-S and SARS2-S. Paradoxically, bromhexine enhanced cell-cell fusion in the presence of TMPRSS2, while its metabolite ambroxol exhibited inhibitory activity under some conditions. On Calu-3 lung cells, ambroxol weakly inhibited SARS2-S-driven lentiviral pseudoparticle entry, and both substances exhibited a dose-dependent trend toward weak inhibition of authentic SARS-CoV-2.IMPORTANCE Cell-cell fusion allows viruses to infect neighboring cells without the need to produce free virus and contributes to tissue damage by creating virus-infected syncytia. Our results demonstrate that the S2' cleavage site is essential for activation by TMPRSS2 and unravel important differences between SARS-CoV and SARS-CoV-2, among those, greater dependence of SARS-CoV-2 on ACE2 expression and activation by metalloproteases for cell-cell fusion. Bromhexine, reportedly an inhibitor of TMPRSS2, is currently being tested in clinical trials against coronavirus disease 2019. Our results indicate that bromhexine enhances fusion under some conditions. We therefore caution against the use of bromhexine in high dosages until its effects on SARS-CoV-2 spike activation are better understood. The related compound ambroxol, which similarly to bromhexine is clinically used as an expectorant, did not exhibit activating effects on cell-cell fusion. Both compounds exhibited weak inhibitory activity against SARS-CoV-2 infection at high concentrations, which might be clinically attainable for ambroxol.
Asunto(s)
COVID-19/metabolismo , SARS-CoV-2/metabolismo , Síndrome Respiratorio Agudo Grave/metabolismo , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Internalización del Virus , Ambroxol/farmacología , Sustitución de Aminoácidos , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/metabolismo , Bromhexina/farmacología , COVID-19/genética , Línea Celular , Humanos , Mutación Missense , Proteolisis/efectos de los fármacos , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/genética , SARS-CoV-2/genética , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , Síndrome Respiratorio Agudo Grave/genética , Glicoproteína de la Espiga del Coronavirus/genéticaRESUMEN
Angiotensin-converting enzyme 2 (ACE2) is the host cellular receptor that locks onto the surface spike protein of the 2002 SARS coronavirus (SARS-CoV-1) and of the novel, highly transmissible and deadly 2019 SARS-CoV-2, responsible for the COVID-19 pandemic. One strategy to avoid the virus infection is to design peptides by extracting the human ACE2 peptidase domain α1-helix, which would bind to the coronavirus surface protein, preventing the virus entry into the host cells. The natural α1-helix peptide has a stronger affinity to SARS-CoV-2 than to SARS-CoV-1. Another peptide was designed by joining α1 with the second portion of ACE2 that is far in the peptidase sequence yet grafted in the spike protein interface with ACE2. Previous studies have shown that, among several α1-based peptides, the hybrid peptidic scaffold is the one with the highest/strongest affinity for SARS-CoV-1, which is comparable to the full-length ACE2 affinity. In this work, binding and folding dynamics of the natural and designed ACE2-based peptides were simulated by the well-known coarse-grained structure-based model, with the computed thermodynamic quantities correlating with the experimental binding affinity data. Furthermore, theoretical kinetic analysis of native contact formation revealed the distinction between these processes in the presence of the different binding partners SARS-CoV-1 and SARS-CoV-2 spike domains. Additionally, our results indicate the existence of a two-state folding mechanism for the designed peptide en route to bind to the spike proteins, in contrast to a downhill mechanism for the natural α1-helix peptides. The presented low-cost simulation protocol demonstrated its efficiency in evaluating binding affinities and identifying the mechanisms involved in the neutralization of spike-ACE2 interaction by designed peptides. Finally, the protocol can be used as a computer-based screening of more potent designed peptides by experimentalists searching for new therapeutics against COVID-19.
Asunto(s)
Enzima Convertidora de Angiotensina 2/metabolismo , Antivirales/farmacología , Tratamiento Farmacológico de COVID-19 , Diseño de Fármacos , Péptidos/farmacología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Antivirales/química , COVID-19/metabolismo , Humanos , Modelos Moleculares , Péptidos/química , Unión Proteica/efectos de los fármacos , Dominios Proteicos/efectos de los fármacos , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/efectos de los fármacos , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/metabolismo , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/metabolismo , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico , Síndrome Respiratorio Agudo Grave/metabolismoRESUMEN
Lymphopenia is commonly observed in SARS and COVID-19 patients although the lymphocyte count is not always below 0.8 × 109 /L in all the patients. It is suggested that lymphopenia serves as a useful predictor for prognosis in the patients. It is also hypothesized that lymphopenia is related to glucocorticoids and apoptosis. However, the ordering between lymphopenia and apoptosis appears different between SARS and COVID-19 patients, ie, lymphopenia is prior to apoptosis in SARS patients whereas apoptosis is prior to lymphopenia in COVID-19 patients. This paper attempts to figure out this contradiction through three players, lymphopenia, glucocorticoids, and apoptosis. Although the literature does not provide a solid explanation, the level of glucocorticoids could determine the ordering between lymphopenia and apoptosis because the administration of high doses of glucocorticoids could lead to lymphopenia whereas low doses of glucocorticoids could benefit patients. In the meantime, this paper raises several questions, which need to be answered in order to better understand the whole course of COVID-19.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , COVID-19 , Glucocorticoides , Linfopenia , SARS-CoV-2/metabolismo , Síndrome Respiratorio Agudo Grave , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/metabolismo , Apoptosis/efectos de los fármacos , COVID-19/complicaciones , COVID-19/metabolismo , Glucocorticoides/efectos adversos , Glucocorticoides/uso terapéutico , Humanos , Linfopenia/tratamiento farmacológico , Linfopenia/etiología , Linfopenia/metabolismo , Síndrome Respiratorio Agudo Grave/complicaciones , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico , Síndrome Respiratorio Agudo Grave/metabolismoRESUMEN
BACKGROUND: The 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. RESULTS: In 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. CONCLUSIONS: H2V 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 .
Asunto(s)
COVID-19/metabolismo , Infecciones por Coronavirus/metabolismo , Bases de Datos Genéticas , Bases de Datos de Proteínas , Síndrome Respiratorio Agudo Grave/metabolismo , Interfaz Usuario-Computador , COVID-19/genética , COVID-19/patología , COVID-19/virología , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Humanos , Coronavirus del Síndrome Respiratorio de Oriente Medio/fisiología , Proteómica , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/fisiología , SARS-CoV-2/fisiología , Síndrome Respiratorio Agudo Grave/genética , Síndrome Respiratorio Agudo Grave/patología , Síndrome Respiratorio Agudo Grave/virologíaRESUMEN
We have reviewed the available literature on thyroid diseases and coronavirus disease 2019 (COVID-19), and data from the previous coronavirus pandemic, the severe acute respiratory syndrome (SARS) epidemic. We learned that both SARS and COVID-19 patients had thyroid abnormalities. In the limited number of SARS cases, where it was examined, decreased serum T3, T4 and TSH levels were detected. In a study of survivors of SARS approximately 7% of the patients had hypothyroidism. In the previous evaluation evidence was found that pituitary function was also affected in SARS. Others suggested a hypothalamic-pituitary-adrenal axis dysfunction. One result published recently indicates that a primary injury to the thyroid gland itself may play a key role in the pathogenesis of thyroid disorders in COVID-19 patients, too. Subacute thyroiditis, autoimmune thyroiditis and an atypical form of thyroiditis are complications of COVID-19. Thyroid hormone dysfunction affects the outcome by increasing mortality in critical illnesses like acute respiratory distress syndrome, which is a leading complication in COVID-19. Angiotensin-converting enzyme 2 is a membrane-bound enzyme, which is also expressed in the thyroid gland and the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) uses it for docking, entering as well as replication. Based on the available results obtained in the SARS-CoV-2 pandemic, beside others, we suggest that it is necessary to monitor thyroid hormones in COVID-19.
Asunto(s)
COVID-19/fisiopatología , Enfermedad de Graves/fisiopatología , Hipotiroidismo/fisiopatología , Síndrome de Dificultad Respiratoria/fisiopatología , Tiroiditis/fisiopatología , Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/complicaciones , COVID-19/metabolismo , Enfermedad de Graves/etiología , Enfermedad de Graves/metabolismo , Humanos , Hipotiroidismo/etiología , Hipotiroidismo/metabolismo , Mortalidad , Pronóstico , Receptores de Coronavirus/metabolismo , Síndrome de Dificultad Respiratoria/etiología , Síndrome de Dificultad Respiratoria/metabolismo , SARS-CoV-2/metabolismo , Síndrome Respiratorio Agudo Grave/complicaciones , Síndrome Respiratorio Agudo Grave/metabolismo , Síndrome Respiratorio Agudo Grave/fisiopatología , Glándula Tiroides/metabolismo , Tiroiditis/etiología , Tiroiditis/metabolismo , Tiroiditis Autoinmune/etiología , Tiroiditis Autoinmune/metabolismo , Tiroiditis Autoinmune/fisiopatología , Tiroiditis Subaguda/etiología , Tiroiditis Subaguda/metabolismo , Tiroiditis Subaguda/fisiopatología , Tirotropina/metabolismo , Tiroxina/metabolismo , Triyodotironina/metabolismoRESUMEN
COVID-19, a new disease caused by the 2019-novel coronavirus (SARS-CoV-2), has swept the world and challenged its culture, economy, and health infrastructure. Forced emergence to find an effective vaccine to immunize people has led scientists to design and examine vaccine candidates all over the world. Until a vaccine is developed, however, effective treatment is needed to combat this virus, which is resistant to all conventional antiviral drugs. Accordingly, more about the structure, entry mechanism, and pathogenesis of COVID-19 is required. Angiotensin-converting enzyme 2 (ACE2) is the gateway to SARS-CoV and SARS-CoV-2, so our knowledge of SARS-CoV-2 can help us to complete its mechanism of interaction with ACE2 and virus endocytosis, which can be interrupted by neutralizing small molecules or proteins. ACE2 also plays a crucial role in lung injury.
Asunto(s)
Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/metabolismo , COVID-19/fisiopatología , SARS-CoV-2/patogenicidad , Internalización del Virus , Humanos , Síndrome Respiratorio Agudo Grave/metabolismo , Síndrome Respiratorio Agudo Grave/fisiopatologíaRESUMEN
The ongoing COVID-19 pandemic caused by the coronavirus, SARS-CoV-2, has already caused in excess of 1.25 million deaths worldwide, and the number is increasing. Knowledge of the host transcriptional response against this virus and how the pathways are activated or suppressed compared to other human coronaviruses (SARS-CoV, MERS-CoV) that caused outbreaks previously can help in the identification of potential drugs for the treatment of COVID-19. Hence, we used time point meta-analysis to investigate available SARS-CoV and MERS-CoV in-vitro transcriptome datasets in order to identify the significant genes and pathways that are dysregulated at each time point. The subsequent over-representation analysis (ORA) revealed that several pathways are significantly dysregulated at each time point after both SARS-CoV and MERS-CoV infection. We also performed gene set enrichment analyses of SARS-CoV and MERS-CoV with that of SARS-CoV-2 at the same time point and cell line, the results of which revealed that common pathways are activated and suppressed in all three coronaviruses. Furthermore, an analysis of an in-vivo transcriptomic dataset of COVID-19 patients showed that similar pathways are enriched to those identified in the earlier analyses. Based on these findings, a drug repurposing analysis was performed to identify potential drug candidates for combating COVID-19.
Asunto(s)
Antivirales , COVID-19/metabolismo , Bases de Datos de Ácidos Nucleicos , Reposicionamiento de Medicamentos , Coronavirus del Síndrome Respiratorio de Oriente Medio/metabolismo , SARS-CoV-2/metabolismo , Síndrome Respiratorio Agudo Grave/metabolismo , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/metabolismo , Transcriptoma , COVID-19/genética , Humanos , Coronavirus del Síndrome Respiratorio de Oriente Medio/genética , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/genética , SARS-CoV-2/genética , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico , Síndrome Respiratorio Agudo Grave/genética , Tratamiento Farmacológico de COVID-19RESUMEN
Coronaviruses represent global health threat. In this century, they have already caused two epidemics and one serious pandemic. Although, at present, there are no approved drugs and therapies for the treatment and prevention of human coronaviruses, several agents, FDA-approved, and preclinical, have shown in vitro and/or in vivo antiviral activity. An in-depth analysis of the current situation leads to the identification of several potential drugs that could have an impact on the fight against coronaviruses infections. In this review, we discuss the virology of human coronaviruses highlighting the main biological targets and summarize the current state-of-the-art of possible therapeutic options to inhibit coronaviruses infections. We mostly focus on FDA-approved and preclinical drugs targeting viral conserved elements.
Asunto(s)
Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/metabolismo , Infecciones por Coronavirus/metabolismo , Coronavirus/metabolismo , Dipeptidil Peptidasa 4/metabolismo , Síndrome Respiratorio Agudo Grave/metabolismo , Enzima Convertidora de Angiotensina 2/antagonistas & inhibidores , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Inhibidores de la Enzima Convertidora de Angiotensina/metabolismo , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/metabolismo , Antivirales/administración & dosificación , Antivirales/metabolismo , Azoles/administración & dosificación , Azoles/metabolismo , Coronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/metabolismo , Humanos , Isoindoles , Naftoquinonas/administración & dosificación , Naftoquinonas/metabolismo , Compuestos de Organoselenio/administración & dosificación , Compuestos de Organoselenio/metabolismo , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico , Tratamiento Farmacológico de COVID-19RESUMEN
Human coronaviruses (hCoVs) have become a threat to global health and society, as evident from the SARS outbreak in 2002 caused by SARS-CoV-1 and the most recent COVID-19 pandemic caused by SARS-CoV-2. Despite a high sequence similarity between SARS-CoV-1 and -2, each strain has a distinctive virulence. A better understanding of the basic molecular mechanisms mediating changes in virulence is needed. Here, we profile the virus-host protein-protein interactions of two hCoV nonstructural proteins (nsps) that are critical for virus replication. We use tandem mass tag-multiplexed quantitative proteomics to sensitively compare and contrast the interactomes of nsp2 and nsp4 from three betacoronavirus strains: SARS-CoV-1, SARS-CoV-2, and hCoV-OC43-an endemic strain associated with the common cold. This approach enables the identification of both unique and shared host cell protein binding partners and the ability to further compare the enrichment of common interactions across homologues from related strains. We identify common nsp2 interactors involved in endoplasmic reticulum (ER) Ca2+ signaling and mitochondria biogenesis. We also identify nsp4 interactors unique to each strain, such as E3 ubiquitin ligase complexes for SARS-CoV-1 and ER homeostasis factors for SARS-CoV-2. Common nsp4 interactors include N-linked glycosylation machinery, unfolded protein response associated proteins, and antiviral innate immune signaling factors. Both nsp2 and nsp4 interactors are strongly enriched in proteins localized at mitochondria-associated ER membranes suggesting a new functional role for modulating host processes, such as calcium homeostasis, at these organelle contact sites. Our results shed light on the role these hCoV proteins play in the infection cycle, as well as host factors that may mediate the divergent pathogenesis of OC43 from SARS strains. Our mass spectrometry workflow enables rapid and robust comparisons of multiple bait proteins, which can be applied to additional viral proteins. Furthermore, the identified common interactions may present new targets for exploration by host-directed antiviral therapeutics.
Asunto(s)
COVID-19/metabolismo , Interacciones Huésped-Patógeno/genética , SARS-CoV-2/patogenicidad , Proteínas no Estructurales Virales/metabolismo , COVID-19/virología , Coronavirus Humano OC43/patogenicidad , Retículo Endoplásmico/metabolismo , Células HEK293 , Humanos , Proteínas de la Membrana/metabolismo , Mitocondrias/metabolismo , Unión Proteica , Mapas de Interacción de Proteínas/genética , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/patogenicidad , Síndrome Respiratorio Agudo Grave/metabolismo , Síndrome Respiratorio Agudo Grave/virología , Transfección , Proteínas no Estructurales Virales/genética , Virulencia/genética , Replicación Viral/genéticaRESUMEN
The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a grave threat to public health and the global economy. SARS-CoV-2 is closely related to the more lethal but less transmissible coronaviruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV). Here, we have carried out comparative viral-human protein-protein interaction and viral protein localization analyses for all three viruses. Subsequent functional genetic screening identified host factors that functionally impinge on coronavirus proliferation, including Tom70, a mitochondrial chaperone protein that interacts with both SARS-CoV-1 and SARS-CoV-2 ORF9b, an interaction we structurally characterized using cryo-electron microscopy. Combining genetically validated host factors with both COVID-19 patient genetic data and medical billing records identified molecular mechanisms and potential drug treatments that merit further molecular and clinical study.