Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 741
Filtrar
1.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073283

RESUMO

Infection induces the production of proinflammatory cytokines and chemokines such as interleukin-8 (IL-8) and IL-6. Although they facilitate local antiviral immunity, their excessive release leads to life-threatening cytokine release syndrome, exemplified by the severe cases of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this study, we investigated the roles of the integrated stress response (ISR) and activator protein-1 (AP-1) family proteins in regulating coronavirus-induced IL-8 and IL-6 upregulation. The mRNA expression of IL-8 and IL-6 was significantly induced in cells infected with infectious bronchitis virus (IBV), a gammacoronavirus, and porcine epidemic diarrhea virus, an alphacoronavirus. Overexpression of a constitutively active phosphomimetic mutant of eukaryotic translation initiation factor 2α (eIF2α), chemical inhibition of its dephosphorylation, or overexpression of its upstream double-stranded RNA-dependent protein kinase (PKR) significantly enhanced IL-8 mRNA expression in IBV-infected cells. Overexpression of the AP-1 protein cJUN or its upstream kinase also increased the IBV-induced IL-8 mRNA expression, which was synergistically enhanced by overexpression of cFOS. Taken together, this study demonstrated the important regulatory roles of ISR and AP-1 proteins in IL-8 production during coronavirus infection, highlighting the complex interactions between cellular stress pathways and the innate immune response.


Assuntos
Infecções por Coronavirus/metabolismo , Estresse do Retículo Endoplasmático/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Interleucina-8/metabolismo , Resposta a Proteínas não Dobradas/genética , Alphacoronavirus/metabolismo , Alphacoronavirus/patogenicidade , Animais , Linhagem Celular , Chlorocebus aethiops , Infecções por Coronavirus/genética , Gammacoronavirus/metabolismo , Gammacoronavirus/patogenicidade , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Vírus da Bronquite Infecciosa/metabolismo , Vírus da Bronquite Infecciosa/patogenicidade , Interleucina-8/genética , Fosforilação , Vírus da Diarreia Epidêmica Suína/metabolismo , Vírus da Diarreia Epidêmica Suína/patogenicidade , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , Transdução de Sinais/genética , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Regulação para Cima , Células Vero , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismo
2.
Viruses ; 13(4)2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808275

RESUMO

Porcine epidemic diarrhea virus (PEDV), an enteropathogenic coronavirus, has catastrophic impacts on the global pig industry. Owing to the lack of effective vaccines and specific therapeutic options for PEDV, it is pertinent to develop new and available antivirals. This study identified, for the first time, a salinomycin that actively inhibited PEDV replication in Vero cells in a dose-dependent manner. Furthermore, salinomycin significantly inhibited PEDV infection by suppressing the entry and post-entry of PEDV in Vero cells. It did not directly interact with or inactivate PEDV particles, but it significantly ameliorated the activation of Erk1/2, JNK and p38MAPK signaling pathways that are associated with PEDV infection. This implied that salinomycin inhibits PEDV replication by altering MAPK pathway activation. Notably, the PEDV induced increase in reactive oxidative species (ROS) was not decreased, indicating that salinomycin suppresses PEDV replication through a pathway that is an independent pathway of viral-induced ROS. Therefore, salinomycin is a potential drug that can be used for treating PEDV infection.


Assuntos
Antivirais/farmacologia , Infecções por Coronavirus/veterinária , Vírus da Diarreia Epidêmica Suína/efeitos dos fármacos , Piranos/farmacologia , Doenças dos Suínos/virologia , Animais , Chlorocebus aethiops , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Sistema de Sinalização das MAP Quinases , Vírus da Diarreia Epidêmica Suína/genética , Vírus da Diarreia Epidêmica Suína/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Suínos , Doenças dos Suínos/tratamento farmacológico , Doenças dos Suínos/genética , Doenças dos Suínos/metabolismo , Células Vero , Replicação Viral/efeitos dos fármacos
3.
Int J Biol Macromol ; 179: 1-19, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33667553

RESUMO

Three coronaviruses (CoVs) have threatened the world population by causing outbreaks in the last two decades. In late 2019, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged and caused the coronaviruses to disease 2019 (COVID-19), leading to the ongoing global outbreak. The other pandemic coronaviruses, SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV), share a considerable level of similarities at genomic and protein levels. However, the differences between them lead to distinct behaviors. These differences result from the accumulation of mutations in the sequence and structure of spike (S) glycoprotein, which plays an essential role in coronavirus infection, pathogenicity, transmission, and evolution. In this review, we brought together many studies narrating a sequence of events and highlighting the differences among S proteins from SARS-CoV, MERS-CoV, and SARS-CoV-2. It was performed here, analysis of S protein sequences and structures from the three pandemic coronaviruses pointing out the mutations among them and what they come through. Additionally, we investigated the receptor-binding domain (RBD) from all S proteins explaining the mutation and biological importance of all of them. Finally, we discuss the mutation in the S protein from several new isolates of SARS-CoV-2, reporting their difference and importance. This review brings into detail how the variations in S protein that make SARS-CoV-2 more aggressive than its relatives coronaviruses and other differences between coronaviruses.


Assuntos
COVID-19/virologia , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/genética , Animais , COVID-19/epidemiologia , COVID-19/metabolismo , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Glicoproteínas/metabolismo , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/metabolismo , Pandemias , Ligação Proteica , Vírus da SARS/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo
4.
Viruses ; 13(2)2021 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-33668405

RESUMO

Porcine deltacoronavirus (PDCoV) is an emerging infectious disease of swine with zoonotic potential. Phylogenetic analysis suggests that PDCoV originated recently from a host-switching event between birds and mammals. Little is known about how PDCoV interacts with its differing hosts. Human-derived cell lines are susceptible to PDCoV infection. Herein, we compare the gene expression profiles of an established host swine cells to potential emerging host human cells after infection with PDCoV. Cell lines derived from intestinal lineages were used to reproduce the primary sites of viral infection in the host. Porcine intestinal epithelial cells (IPEC-J2) and human intestinal epithelial cells (HIEC) were infected with PDCoV. RNA-sequencing was performed on total RNA extracted from infected cells. Human cells exhibited a more pronounced response to PDCoV infection in comparison to porcine cells with more differentially expressed genes (DEGs) in human, 7486, in comparison to pig cells, 1134. On the transcriptional level, the adoptive host human cells exhibited more DEGs in response to PDCoV infection in comparison to the primary pig host cells, where different types of cytokines can control PDCoV replication and virus production. Key immune-associated DEGs and signaling pathways are shared between human and pig cells during PDCoV infection. These included genes related to the NF-kappa-B transcription factor family, the interferon (IFN) family, the protein-kinase family, and signaling pathways such as the apoptosis signaling pathway, JAK-STAT signaling pathway, inflammation/cytokine-cytokine receptor signaling pathway. MAP4K4 was unique in up-regulated DEGs in humans in the apoptosis signaling pathway. While similarities exist between human and pig cells in many pathways, our research suggests that the adaptation of PDCoV to the porcine host required the ability to down-regulate many response pathways including the interferon pathway. Our findings provide an important foundation that contributes to an understanding of the mechanisms of PDCoV infection across different hosts. To our knowledge, this is the first report of transcriptome analysis of human cells infected by PDCoV.


Assuntos
Infecções por Coronavirus/metabolismo , Células Epiteliais/virologia , Doenças dos Suínos/metabolismo , Transcriptoma , Animais , Linhagem Celular , Citocinas/metabolismo , Regulação da Expressão Gênica , Humanos , Interferons/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Suínos
5.
Infect Dis Poverty ; 10(1): 28, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33726861

RESUMO

BACKGROUND: Coronaviruses (CoVs) are distributed worldwide and have various susceptible hosts; CoVs infecting humans are called human coronaviruses (HCoVs). Although HCoV-specific drugs are still lacking, many potent targets for drug discovery are being explored, and many vigorously designed clinical trials are being carried out in an orderly manner. The aim of this review was to gain a comprehensive understanding of the current status of drug development against HCoVs, particularly severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). MAIN TEXT: A scoping review was conducted by electronically searching research studies, reviews, and clinical trials in PubMed and the CNKI. Studies on HCoVs and therapeutic drug discovery published between January 2000 and October 2020 and in English or Chinese were included, and the information was summarized. Of the 3248 studies identified, 159 publication were finally included. Advances in drug development against HCoV, especially SARS-CoV-2, are summarized under three categories: antiviral drugs aimed at inhibiting the HCoV proliferation process, drugs acting on the host's immune system, and drugs derived from plants with potent activity. Furthermore, clinical trials of drugs targeting SARS-CoV-2 are summarized. CONCLUSIONS: During the spread of COVID-19 outbreak, great efforts have been made in therapeutic drug discovery against the virus, although the pharmacological effects and adverse reactions of some drugs under study are still unclear. However, well-designed high-quality studies are needed to further study the effectiveness and safety of these potential drugs so as to provide valid recommendations for better control of the COVID-19 pandemic.


Assuntos
Antivirais/farmacologia , Infecções por Coronavirus/virologia , Coronavirus/efeitos dos fármacos , Coronavirus/fisiologia , Descoberta de Drogas , Antivirais/uso terapêutico , Biomarcadores , COVID-19/tratamento farmacológico , COVID-19/metabolismo , COVID-19/virologia , Coronavirus/classificação , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Desenvolvimento de Medicamentos , Descoberta de Drogas/métodos , Regulação Viral da Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Medicina Tradicional , Terapia de Alvo Molecular , SARS-CoV-2/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
6.
J Virol ; 95(9)2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33568512

RESUMO

Porcine epidemic diarrhea virus (PEDV) is an α-coronavirus causing severe diarrhea and high mortality rates in suckling piglets and posing significant economic impact. PEDV replication is completed and results in a large amount of RNA in the cytoplasm. Stress granules (SGs) are dynamic cytosolic RNA granules formed under various stress conditions, including viral infections. Several previous studies suggested that SGs were involved in the antiviral activity of host cells to limit viral propagation. However, the underlying mechanisms are poorly understood. This study aimed to delineate the molecular mechanisms regulating the SG response to PEDV infection. SG formation is induced early during PEDV infection, but as infection proceeds, this ability is lost and SGs disappear at late stages of infection (>18 h postinfection). PEDV infection resulted in the cleavage of Ras-GTPase-activating protein-binding protein 1 (G3BP1) mediated by caspase-8. Using mutational analysis, the PEDV-induced cleavage site within G3BP1 was identified, which differed from the 3C protease cleavage site previously identified. Furthermore, G3BP1 cleavage by caspase-8 at D168 and D169 was confirmed in vitro as well as in vivo The overexpression of cleavage-resistant G3BP1 conferred persistent SG formation and suppression of viral replication. Additionally, the knockdown of endogenous G3BP1 abolished SG formation and potentiated viral replication. Taken together, these data provide new insights into novel strategies in which PEDV limits the host stress response and antiviral responses and indicate that caspase-8-mediated G3BP1 cleavage is important in the failure of host defense against PEDV infection.IMPORTANCE Coronaviruses (CoVs) are drawing extensive attention again since the outbreaks of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019. CoVs are prone to variation and own the transmission capability by crossing the species barrier resulting in reemergence. How CoVs manipulate the antiviral responses of their hosts needs to be explored. Overall, the study provides new insight into how porcine epidemic diarrhea virus (PEDV) impaired SG assembly by targeting G3BP1 via the host proteinase caspase-8. These findings enhanced the understanding of PEDV infection and might help identify new antiviral targets that could inhibit viral replication and limit the pathogenesis of PEDV.


Assuntos
Caspase 8/metabolismo , Infecções por Coronavirus/metabolismo , Grânulos Citoplasmáticos/metabolismo , Vírus da Diarreia Epidêmica Suína/fisiologia , Proteólise , Proteínas com Motivo de Reconhecimento de RNA/metabolismo , Replicação Viral , Animais , Caspase 8/genética , Chlorocebus aethiops , Infecções por Coronavirus/genética , Infecções por Coronavirus/patologia , Grânulos Citoplasmáticos/genética , Grânulos Citoplasmáticos/virologia , Células HEK293 , Humanos , Proteínas com Motivo de Reconhecimento de RNA/genética , Suínos , Células Vero
7.
Int J Mol Sci ; 22(3)2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33525632

RESUMO

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a novel epidemic strain of Betacoronavirus that is responsible for the current viral pandemic, coronavirus disease 2019 (COVID-19), a global health crisis. Other epidemic Betacoronaviruses include the 2003 SARS-CoV-1 and the 2009 Middle East Respiratory Syndrome Coronavirus (MERS-CoV), the genomes of which, particularly that of SARS-CoV-1, are similar to that of the 2019 SARS-CoV-2. In this extensive review, we document the most recent information on Coronavirus proteins, with emphasis on the membrane proteins in the Coronaviridae family. We include information on their structures, functions, and participation in pathogenesis. While the shared proteins among the different coronaviruses may vary in structure and function, they all seem to be multifunctional, a common theme interconnecting these viruses. Many transmembrane proteins encoded within the SARS-CoV-2 genome play important roles in the infection cycle while others have functions yet to be understood. We compare the various structural and nonstructural proteins within the Coronaviridae family to elucidate potential overlaps and parallels in function, focusing primarily on the transmembrane proteins and their influences on host membrane arrangements, secretory pathways, cellular growth inhibition, cell death and immune responses during the viral replication cycle. We also offer bioinformatic analyses of potential viroporin activities of the membrane proteins and their sequence similarities to the Envelope (E) protein. In the last major part of the review, we discuss complement, stimulation of inflammation, and immune evasion/suppression that leads to CoV-derived severe disease and mortality. The overall pathogenesis and disease progression of CoVs is put into perspective by indicating several stages in the resulting infection process in which both host and antiviral therapies could be targeted to block the viral cycle. Lastly, we discuss the development of adaptive immunity against various structural proteins, indicating specific vulnerable regions in the proteins. We discuss current CoV vaccine development approaches with purified proteins, attenuated viruses and DNA vaccines.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/metabolismo , Proteínas da Matriz Viral/metabolismo , Animais , Betacoronavirus/genética , Betacoronavirus/imunologia , COVID-19/imunologia , COVID-19/metabolismo , COVID-19/patologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Genoma Viral , Interações Hospedeiro-Patógeno , Humanos , Evasão da Resposta Imune , Mapas de Interação de Proteínas , SARS-CoV-2/genética , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Proteínas da Matriz Viral/genética , Proteínas da Matriz Viral/imunologia , Internalização do Vírus , Replicação Viral
8.
PLoS One ; 16(2): e0246901, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33596252

RESUMO

The MERS-CoV, SARS-CoV, and SARS-CoV-2 are highly pathogenic viruses that can cause severe pneumonic diseases in humans. Unfortunately, there is a non-available effective treatment to combat these viruses. Domain-motif interactions (DMIs) are an essential means by which viruses mimic and hijack the biological processes of host cells. To disentangle how viruses achieve this process can help to develop new rational therapies. Data mining was performed to obtain DMIs stored as regular expressions (regexp) in 3DID and ELM databases. The mined regexp information was mapped on the coronaviruses' proteomes. Most motifs on viral protein that could interact with human proteins are shared across the coronavirus species, indicating that molecular mimicry is a common strategy for coronavirus infection. Enrichment ontology analysis for protein domains showed a shared biological process and molecular function terms related to carbon source utilization and potassium channel regulation. Some of the mapped motifs were nested on B, and T cell epitopes, suggesting that it could be as an alternative way for reverse vaccinology. The information obtained in this study could be used for further theoretic and experimental explorations on coronavirus infection mechanism and development of medicines for treatment.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Mimetismo Molecular/fisiologia , Domínios e Motivos de Interação entre Proteínas/imunologia , Betacoronavirus/genética , COVID-19/metabolismo , COVID-19/virologia , Infecções por Coronavirus/genética , Bases de Dados Genéticas , Interações Hospedeiro-Patógeno , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/metabolismo , Domínios Proteicos , Domínios e Motivos de Interação entre Proteínas/genética , Proteoma , Vírus da SARS/genética , Vírus da SARS/metabolismo , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Proteínas Virais/metabolismo
9.
Sci Rep ; 11(1): 4108, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33602998

RESUMO

In December 2019, rising pneumonia cases caused by a novel ß-coronavirus (SARS-CoV-2) occurred in Wuhan, China, which has rapidly spread worldwide, causing thousands of deaths. The WHO declared the SARS-CoV-2 outbreak as a public health emergency of international concern, since then several scientists are dedicated to its study. It has been observed that many human viruses have codon usage biases that match highly expressed proteins in the tissues they infect and depend on the host cell machinery for the replication and co-evolution. In this work, we analysed 91 molecular features and codon usage patterns for 339 viral genes and 463 human genes that consisted of 677,873 codon positions. Hereby, we selected the highly expressed genes from human lung tissue to perform computational studies that permit to compare their molecular features with those of SARS, SARS-CoV-2 and MERS genes. The integrated analysis of all the features revealed that certain viral genes and overexpressed human genes have similar codon usage patterns. The main pattern was the A/T bias that together with other features could propitiate the viral infection, enhanced by a host dependant specialization of the translation machinery of only some of the overexpressed genes. The envelope protein E, the membrane glycoprotein M and ORF7 could be further benefited. This could be the key for a facilitated translation and viral replication conducting to different comorbidities depending on the genetic variability of population due to the host translation machinery. This is the first codon usage approach that reveals which human genes could be potentially deregulated due to the codon usage similarities between the host and the viral genes when the virus is already inside the human cells of the lung tissues. Our work leaded to the identification of additional highly expressed human genes which are not the usual suspects but might play a role in the viral infection and settle the basis for further research in the field of human genetics associated with new viral infections. To identify the genes that could be deregulated under a viral infection is important to predict the collateral effects and determine which individuals would be more susceptible based on their genetic features and comorbidities associated.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Códon/genética , Uso do Códon , Biologia Computacional/métodos , Coronavirus/genética , Infecções por Coronavirus/metabolismo , Genes Virais , Genoma Viral , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Filogenia , Vírus da SARS/genética , SARS-CoV-2/genética
10.
BMC Biol ; 19(1): 12, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33482803

RESUMO

BACKGROUND: Pandemics, even more than other medical problems, require swift integration of knowledge. When caused by a new virus, understanding the underlying biology may help finding solutions. In a setting where there are a large number of loosely related projects and initiatives, we need common ground, also known as a "commons." Wikidata, a public knowledge graph aligned with Wikipedia, is such a commons and uses unique identifiers to link knowledge in other knowledge bases. However, Wikidata may not always have the right schema for the urgent questions. In this paper, we address this problem by showing how a data schema required for the integration can be modeled with entity schemas represented by Shape Expressions. RESULTS: As a telling example, we describe the process of aligning resources on the genomes and proteomes of the SARS-CoV-2 virus and related viruses as well as how Shape Expressions can be defined for Wikidata to model the knowledge, helping others studying the SARS-CoV-2 pandemic. How this model can be used to make data between various resources interoperable is demonstrated by integrating data from NCBI (National Center for Biotechnology Information) Taxonomy, NCBI Genes, UniProt, and WikiPathways. Based on that model, a set of automated applications or bots were written for regular updates of these sources in Wikidata and added to a platform for automatically running these updates. CONCLUSIONS: Although this workflow is developed and applied in the context of the COVID-19 pandemic, to demonstrate its broader applicability it was also applied to other human coronaviruses (MERS, SARS, human coronavirus NL63, human coronavirus 229E, human coronavirus HKU1, human coronavirus OC4).


Assuntos
COVID-19/patologia , Genômica/métodos , Bases de Conhecimento , Proteômica/métodos , SARS-CoV-2/fisiologia , COVID-19/metabolismo , COVID-19/virologia , Coronavirus/genética , Coronavirus/fisiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Genoma Viral , Humanos , Internet , Pandemias , SARS-CoV-2/genética , Proteínas Virais/genética , Proteínas Virais/metabolismo , Fluxo de Trabalho
11.
BMC Bioinformatics ; 22(1): 18, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33413085

RESUMO

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 .


Assuntos
COVID-19/metabolismo , Infecções por Coronavirus/metabolismo , Bases de Dados Genéticas , Bases de Dados de Proteínas , Síndrome Respiratória Aguda Grave/metabolismo , Interface Usuário-Computador , COVID-19/genética , COVID-19/patologia , COVID-19/virologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Proteômica , Vírus da SARS/fisiologia , SARS-CoV-2/fisiologia , Síndrome Respiratória Aguda Grave/genética , Síndrome Respiratória Aguda Grave/patologia , Síndrome Respiratória Aguda Grave/virologia
12.
Virology ; 556: 1-8, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33515858

RESUMO

Porcine deltacoronavirus (PDCoV) is one of the emerged coronaviruses posing a significant threat to the swine industry. Previous work showed the presence of a viral accessory protein NS6 in PDCoV-infected cells. In this study, we detected the expression of the NS6 protein in small intestinal tissues of PDCoV-infected piglets. In addition, SDS-PAGE and Western blot analysis of sucrose gradient-purified virions showed the presence of a 13-kDa NS6 protein. Further evidences of the presence of NS6 in the PDCoV virions were obtained by immunogold staining of purified virions with anti-NS6 antiserum, and by immunoprecipitation of NS6 from purified virions. Finally, the anti-NS6 antibody was not able to neutralize PDCoV in cultured cells. These data establish for the first time that the accessory protein NS6 is expressed during infection in vivo and incorporated into PDCoV virions.


Assuntos
Infecções por Coronavirus/veterinária , Deltacoronavirus/metabolismo , Doenças dos Suínos/virologia , Proteínas não Estruturais Virais/metabolismo , Vírion/metabolismo , Animais , Anticorpos Antivirais/imunologia , Linhagem Celular , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/virologia , Camundongos , Coelhos , Suínos , Doenças dos Suínos/metabolismo , Proteínas não Estruturais Virais/imunologia
13.
Mol Biol Rep ; 48(2): 1763-1771, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33483864

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to the outbreak of coronavirus disease 2019 (COVID-19), a worldwide epidemic disease affecting increasing number of patients. Although the virus primarily targets respiratory system, cardiovascular involvement has been reported in accumulating studies. In this review, we first describe the cardiac disorders in human with various types of CoV infection, and in animals infected with coronavirus. Particularly, we will focus on the association of cardiovascular disorders upon SARS-CoV-2 infection, and prognostic cardiac biomarkers in COVID-19. Besides, we will discuss the possible mechanisms underlying cardiac injury resulted from SARS-CoV-2 infection including direct myocardial injury caused by viral infection, reduced level of ACE2, and inflammatory response during infection. Improved understandings of cardiac disorders associated with COVID-19 might predict clinical outcome and provide insights into more rational treatment responses in clinical practice.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Biomarcadores/metabolismo , COVID-19/metabolismo , Doenças Cardiovasculares/metabolismo , SARS-CoV-2/isolamento & purificação , Animais , COVID-19/complicações , COVID-19/virologia , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/diagnóstico , Infecções por Coronavirus/complicações , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Interações Hospedeiro-Patógeno , Humanos , Prognóstico , SARS-CoV-2/fisiologia
14.
Ann Med ; 53(1): 227-236, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33345626

RESUMO

The coronavirus disease-2019 (COVID-19), an infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2), has hit the world very hard by affecting millions of people across countries hence posing a major health threat on a global scale. This novel virus is thought to enter and cause infection in its host through the attachment of its structural protein known as the S-glycoprotein to angiotensin-converting enzyme 2 (ACE2). Given the rapid spread of COVID-19 with its consequences globally, it is mandatory that health caregivers and researchers across all disciplines abreast themselves with the potential effects that this novel virus may have on their fields and the medical society at large. During the infection, the cardiovascular system is affected by unknown pathomechanistic processes, hence accounting for an increased prevalence of cardiovascular diseases (CVDs) among COVID-19 patients. As cardiovascular researchers, we are more concerned about the cardiovascular aspect of SARS-CoV-2/COVID-19. Hence, this concise review addresses these aspects where CVD as a risk factor of COVID-19, the prevalence of CVDs in COVID-19, and the potential cardiovascular disorders which may evolve owing to COVID-19 are discussed. A better understanding of these issues will be pivotal to improve cardiovascular health during this SARS-CoV-2/COVID-19 pandemic and beyond.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , Infecções por Coronavirus/metabolismo , Endotélio Vascular/metabolismo , SARS-CoV-2/metabolismo , COVID-19/fisiopatologia , Infecções por Coronavirus/fisiopatologia , Humanos , Sistema Renina-Angiotensina
15.
Pharmacol Res Perspect ; 9(1): e00691, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33378565

RESUMO

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.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , Infecções por Coronavirus/metabolismo , Coronavirus/metabolismo , Dipeptidil Peptidase 4/metabolismo , Síndrome Respiratória Aguda Grave/metabolismo , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/metabolismo , Antivirais/administração & dosagem , Antivirais/metabolismo , Azóis/administração & dosagem , Azóis/metabolismo , COVID-19/tratamento farmacológico , Coronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/metabolismo , Humanos , Naftoquinonas/administração & dosagem , Naftoquinonas/metabolismo , Compostos Organosselênicos/administração & dosagem , Compostos Organosselênicos/metabolismo , Síndrome Respiratória Aguda Grave/tratamento farmacológico
16.
Microb Pathog ; 150: 104719, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33373693

RESUMO

The recent outbreak of Covid-19 is posing a severe threat to public health globally. Coronaviruses (CoVs) are the largest known group of positive-sense RNA viruses surviving on an extensive number of natural hosts. CoVs are enveloped and non-segmented viruses with a size between 80 and 120 nm. CoV attachment to the surface receptor and its subsequent entrance into cells is mediated by Spike glycoprotein (S). For enhanced CoV entry and successful pathogenesis of CoV, proteolytic processing and receptor-binding act synergistically for induction of large-scale S conformational changes. The shape, size and orientation of receptor-binding domains in viral attachment proteins are well conserved among viruses of different classes that utilize the same receptor. Therefore, investigations unraveling the distribution of cellular receptors with respect to CoV entry, structural aspects of glycoproteins and related conformational changes are highly significant for understanding virus invasion and infection spread. We present the characteristic features of CoV S-Proteins, their significance for CoVs and related receptor binding activities for pathogenesis and viral survival. We are analyzing the novel role of S-protein of CoVs along with their interactive receptors for improving host immunity and decreasing infection spread. This is hoped that presented information will open new ways in tackling coronavirus, especially for the ongoing epidemic.


Assuntos
Infecções por Coronavirus/virologia , Coronavirus/fisiologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Sítios de Ligação , COVID-19/tratamento farmacológico , COVID-19/metabolismo , COVID-19/virologia , Coronavirus/genética , Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Humanos , Ligação Proteica , Conformação Proteica , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Internalização do Vírus , Replicação Viral
17.
Viruses ; 13(1)2020 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-33375371

RESUMO

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) poses a persistent threat to global public health. Although primarily a respiratory illness, extrapulmonary manifestations of COVID-19 include gastrointestinal, cardiovascular, renal and neurological diseases. Recent studies suggest that dysfunction of the endothelium during COVID-19 may exacerbate these deleterious events by inciting inflammatory and microvascular thrombotic processes. Although controversial, there is evidence that SARS-CoV-2 may infect endothelial cells by binding to the angiotensin-converting enzyme 2 (ACE2) cellular receptor using the viral Spike protein. In this review, we explore current insights into the relationship between SARS-CoV-2 infection, endothelial dysfunction due to ACE2 downregulation, and deleterious pulmonary and extra-pulmonary immunothrombotic complications in severe COVID-19. We also discuss preclinical and clinical development of therapeutic agents targeting SARS-CoV-2-mediated endothelial dysfunction. Finally, we present evidence of SARS-CoV-2 replication in primary human lung and cardiac microvascular endothelial cells. Accordingly, in striving to understand the parameters that lead to severe disease in COVID-19 patients, it is important to consider how direct infection of endothelial cells by SARS-CoV-2 may contribute to this process.


Assuntos
COVID-19/metabolismo , Células Endoteliais/metabolismo , Endotélio/metabolismo , SARS-CoV-2/imunologia , Proteína ADAM17/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/uso terapêutico , COVID-19/imunologia , Coronavirus , Infecções por Coronavirus/metabolismo , Células Endoteliais/imunologia , Endotélio/imunologia , Endotélio/virologia , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Humanos , Pulmão/metabolismo , Trombose , Replicação Viral
18.
Database (Oxford) ; 20202020 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-33216893

RESUMO

DPL (http://www.peptide-ligand.cn/) is a comprehensive database of peptide ligand (DPL). DPL1.0 holds 1044 peptide ligand entries and provides references for the study of the polypeptide platform. The data were collected from PubMed-NCBI, PDB, APD3, CAMPR3, etc. The lengths of the base sequences are varied from 3 to78. DPL database has 923 linear peptides and 88 cyclic peptides. The functions of peptides collected by DPL are very wide. It includes 540 entries of antiviral peptides (including SARS-CoV-2), 55 entries of signal peptides, 48 entries of protease inhibitors, 45 entries of anti-hypertension, 37 entries of anticancer peptides, etc. There are 270 different kinds of peptide targets. All peptides in DPL have clear binding targets. Most of the peptides and receptors have 3D structures experimentally verified or predicted by CYCLOPS, I-TASSER and SWISS-MODEL. With the rapid development of the COVID-2019 epidemic, this database also collects the research progress of peptides against coronavirus. In conclusion, DPL is a unique resource, which allows users easily to explore the targets, different structures as well as properties of peptides.


Assuntos
Antivirais/química , Betacoronavirus/química , Bases de Dados de Produtos Farmacêuticos , Bases de Dados de Proteínas , Modelos Moleculares , Peptídeos/química , Sequência de Aminoácidos , Betacoronavirus/genética , Betacoronavirus/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Domínios Proteicos
19.
J Transl Med ; 18(1): 441, 2020 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-33218357

RESUMO

The novel coronavirus disease (COVID-19) is posing a serious challenge to the health-care systems worldwide, with an enormous impact on health conditions and loss of lives. Notably, obesity and its related comorbidities are strictly related with worse clinical outcomes of COVID-19 disease. Recently, there is a growing interest in the clinical use of ketogenic diets (KDs), particularly in the context of severe obesity with related metabolic complications. KDs have been proven effective for a rapid reduction of fat mass, preserving lean mass and providing an adequate nutritional status. In particular, the physiological increase in plasma levels of ketone bodies exerts important anti-inflammatory and immunomodulating effects, which may reveal as precious tools to prevent infection and potential adverse outcomes of COVID-19 disease. We discuss here the importance of KDs for a rapid reduction of several critical risk factors for COVID-19, such as obesity, type 2 diabetes and hypertension, based on the known effects of ketone bodies on inflammation, immunity, metabolic profile and cardiovascular function. We do believe that a rapid reduction of all modifiable risk factors, especially obesity with its metabolic complications, should be a pillar of public health policies and interventions, in view of future waves of SARS-CoV-2 infection.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/metabolismo , Dieta Cetogênica , Glucose/metabolismo , Cetonas/metabolismo , Pneumonia Viral/metabolismo , Infecções por Coronavirus/imunologia , Humanos , Inflamação/patologia , Pandemias , Pneumonia Viral/imunologia
20.
Int J Mol Sci ; 21(22)2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-33203141

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) determines the angiotensin converting enzyme 2 (ACE2) down-regulation and related decrease in angiotensin II degradation. Both these events trigger "cytokine storm" leading to acute lung and cardiovascular injury. A selective therapy for COVID-19 has not yet been identified. Clinical trials with remdesivir gave discordant results. Thus, healthcare systems have focused on "multi-targeted" therapeutic strategies aiming at relieving systemic inflammation and thrombotic complications. No randomized clinical trial has demonstrated the efficacy of renin angiotensin system antagonists in reducing inflammation related to COVID-19. Dexamethasone and tocilizumab showed encouraging data, but their use needs to be further validated. The still-controversial efficacy of these treatments highlighted the importance of organ injury prevention in COVID-19. Neprilysin (NEP) might be an interesting target for this purpose. NEP expression is increased by cytokines on lung fibroblasts surface. NEP activity is elevated in acute respiratory distress syndrome and it is conceivable that it is also high in COVID-19. NEP is implicated in the degradation of natriuretic peptides, bradykinin, substance P, adrenomedullin, and apelin that account for prevention of organ injury. Thus, NEP/angiotensin receptor type 1 (AT1R) inhibitor sacubitril/valsartan (SAC/VAL) may increase levels of these molecules and block AT1Rs required for ACE2 endocytosis in SARS-CoV-2 infection. Moreover, SAC/VAL has a positive impact on acute heart failure that is very frequently observed in deceased COVID-19 patients. The current review aims to summarize actual therapeutic strategies for COVID-19 and to examine the data supporting the potential benefits of SAC/VAL in COVID-19 treatment.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Neprilisina/antagonistas & inibidores , Pneumonia Viral/tratamento farmacológico , Aminobutiratos/administração & dosagem , Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/administração & dosagem , Animais , Infecções por Coronavirus/metabolismo , Combinação de Medicamentos , Humanos , Neprilisina/metabolismo , Pandemias , Pneumonia Viral/metabolismo , Tetrazóis/administração & dosagem , Tetrazóis/uso terapêutico , Valsartana/administração & dosagem , Valsartana/uso terapêutico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...